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Tooth extractions in hemophiliacs
OriginalReports
Int. J. Oral Surg. 1975: 4:1-17 (Key words: bleeding; hemophilia; hemorrhage; tooth extraction)
Tooth extractions in hemophiliacs GORAN RAMSTROM A N D M A R G A R E T A BLOMB.KCK
Department of Oral and Jaw Diseases and Department of Blood Coagulation, Karolinska S]ukhuset, Stockholm, Sweden
Patients with tendency to bleed can raise considerable problems in oral surgery. A total of 264 teeth and root stumps were extracted in 67 patients with hemophilia A, hemophilia B and yon Willebrand's disease in 118 treatment sessions. An additional four patients with rare coagulation defects were treated. The patient material is divided into three groups in respect to therapy. Patients in Group 1 were given substitution therapy only in connection with the extractions. In Group 2 this form of treatment was supported by fibrinolytic inhibitors and antibiotics, and in Group 3 local hemostatic treatment of the alveolus and acrylic splints were added. It is shown how the substitution therapy and the number of hospitalization days can be markedly reduced, and the postoperative bleedings lessened by changing from treatment according to Group 1 to Group 2, respectively Group 3. It is pointed out that the coagulum formed in the alveolus must be protected from traumatic influence and against the unfavorable influence of saliva by using acrylic splints. Finally, the importance of decreasing local proteolysis through fibrinolytic inhibitors and of reducing postoperative infections by the use of antibiotics has been emphasized. ABSTRACT
- -
(Received for publication 20 March, accepted 15 September 1974)
I n patients with hereditary hemophilia, such as hemophilia A (Factor VIII deficiency), hemophilia B (Factor I X deficiency) or other coagulation disorders, the bleeding risk in tooth extraction is great and the bleeding can prove fatal a~. This applies particularly to the severe ( < 1 % of the factor content; normal range for Factor VIII 65135 % and for Factor IX 60-160 %) and moderate forms (1-5 % of the factor content) of the diseases in question a~. This is also the case in yon Willebrand's diseaseS7 (Table 1). As far as bleeding risks in major surgical intervention are concerned, the
moderate forms can be grouped with the severe forms mentioned above. In the patient material presented by R,MOReNa2 there were also many cases of the mild forms ( > 5 % of the factor content), and experience showed that in these patients, too, considerably increased bleeding was fiwolved in tooth extraction, as well. These mild coagulation disorders are often not diagnosed until a postoperative bleeding occurs, such as following a tooth extraction. Thus, it can be the dentist who discovers the coagulation disorder in the patient suffering from the mild coagulation defectk
2
RAMSTRCJM AND BLOMBN.CK
Table 1. Tooth extractions in patients with hemophilia A and B and yon Willebrand's disease
Author
Year
Bleeding disorder
Ramgren 82
1962
Hemophilia A severe moderate mild Hemophilia B severe moderate mild
Buchanan 8 LeavelP ~ Silwer a7
1956
v. Willebrand's disease
1973
No. of patients
No. of patients reporting bleeding after tooth extraction
71 28 34
12 17 23
19 10 14
10 5 8
95 men 104 women 261"
27 38 134
* 213 patients of the 261 had not received prophylactic treatment (plasma or factor-concentrates). Of these, 131 reported bleedings.
In m a n y hemophiliacs the fear of visits to the d e n t i s t and the resultant bleeding leads to l o n g periods o f dental neglect and i n a d e q u a t e dental care. WEBSTER, ROBERTS & PENICK4~ p o i n t out that "The decayed, missing, filled ( D M F ) rate is considered to be high f o r this young population (average age 20 years). T h e high number o f carious surfaces (D rate), as compared with the n u m b e r o f filled surfaces, indicates that these p a t i e n t s had received little dental care". T h e investigation thus shows that h e m o p h i l i a c subjects p r o b a b l y have a higher caries f r e q u e n c y than other patients who are n o r m M as regards coagulation. This in all l i k e l i h o o d depends on the fact that the former f e a r the often prolonged oozing bleedings which can ensue, even after normal toothbrushing. Therefore, they are frequently less meticulous in their oral hygiene, whereby t h e risk for advanced caries increases c o n s i d e r a b l y with resulting infectious processes and periodontal diseases ~5. Periodontal disease thus advances m o r e rapidly,
which can also entail an increased risk f o r severe acute complications. H e m o p h i l i a c patients therefore form a group where prophylaxis and motivation for a scrupulous oral hygiene are infinitely i m p o r t a n t in t h e reduction of caries and periodontal disease ~. The probable higher caries frequency in hemophiliac patients m a y also be closely related to the fact that the dentist too is faced with increased difficulty when treating these patients '1~. T h e risk of causing lacerations and injury to the mucous m e m brane of the mouth means that a m o r e extensive caries therapy cannot always b e undertaken. It is of vital i m p o r t a n c e t h a t the dental care of hemophiliac patients should b e in the hands of dentists thoroughly familiar with their specific problems. This cannot be over-emphasized 45. One group of hemophiliac patients p a r tictdarly susceptible to gingival bleeding, is that suffering from yon Willebrand's disease. These patients, in addition to their F a c t o r V I I I deficiency, have a p l a s m a factor defect
TOOTH EXTRACTIONS IN HEMOPHILIACS resulting in decreased vascular hemostasis and prolonged bleeding time. This leads to (in addition to hemophilia-like bleedings) an increased tendency towards bleeding from the mucous membranes, resulting in gastrointestinal bleeding, increased and profuse menstrual bleeding and prolonged and irritating gingival bleeding. Patients with severe forms of yon Willebrand's disease are not as common as those with hemophilia A and B, although the number of patients suffering from the mild form is very great. The frequency of bleedings after tooth extraction in this disease is approximately 50 %, according to SILWER'S~7investigations of 1973. As far as the frequency figures for bleedings after tooth extraction are concerned, as given in Table 1 for severe and moderate cases of hemophilia A and B, it should be mentioned that these patients are often aware that they have a coagulation defect before they visit the dentist. Thus, they often are treated prophylactically prior to the tooth extraction, and therefore bleeding complications are fewer than among the mild cases. In the mild group, as previously mentioned, bleeding in connection with tooth extraction is often the first symptom. Thus, as a rule the figures presented are for untreated patients. The figures mentioned by SILWER'~37 above for bleeding complications in yon Willebrand patients shbuld therefore always be seen against this background. SILW,ma7 also reports prophylactic treatment with plasma and factor concentrate upon extractions in 34 of 68 patients. Despite this treatment, eight of these patients afterwards suffered from diffuse bleedtrigs. The introduction of plasma and plasma factor concentrate in the treatment of patients with coagulation disorders has meant much when it comes to reducing the risks of postoperative bleeding. Fresh blood transfusions are usually insufficient to achieve a local hemostasis on tooth extraction 17. It
is naturally better to treat with (fresh) plasma, whereby a greater factor volume can be added with less risk of hypervolemia and congestive heart failurel,10. Often, however, neither is sufficient and one has to resort to treatment with factor concentrate, thanks to which it is now possible to undertake more extensive surgical operations on hemophiliacs, as welllL so. In addition, it must be remembered that the risk of allergic reaction is always present in blood and plasma transfusions. Patients with severe hemophilia A and B can also develop antibody activity (circulating anticoagulants) when treated with blood, plasma or factor concentrate. Furthermore, in all transfusion treatments there remains the risk of transmitting hepatic infection 1~. Different methods have been presented for infusing the lacking factor into patients with coagulation disorders. The most common method, intermittent substitution treatment, implies that the patient receives repeated infusions of plasma or factor concentrate over several days. Here, however, the plasma factor level will vary and if the value is too low, the risk of postoperative bleeding stilt remains. This form of substitution treatment in tooth extraction has been presented by BLOMBXCK& NILSSONs, BJSRLIN & NILSSON-%Zand others. In 1970, M c MILLAN, WEBSTER, ROBERTS ~; BLYTHE23 presented a method for continuous intravenous substitution treatment using a special factor concentrate; this meant that the plasma factor level could be kept constant at the required level. This method is complicated, particularly for the patient, and can hardlsr be considered suitable for routine use. Good results with the fibrinolytic inhibitor E A C A (Epsikapron| in the fibrinolytic bleeding condition have previously been reported 2s. RE~t), LUCAS, FRANSISCO,GEISLER & ERSLEVs3 reported that E A C A had a good bleeding inhibiting effect in tooth
RAMSTROM AND BLOMBXCK extraction. Several other authors, too, have emphasized the importance of E A C A in tooth extraction, with or without substitution therapy.%~,za,4e,4,% WEBSTER, McMmLAN, LUCAS ,& ROBERTS44 showed in 1971 that a high single infusion of Factor VIII - or Factor IX - concentrate complemented with a fibrinolytic inhibitor (EACA) gave good results in tooth extraction. Treatment in accordance with this method has also been used by BJ~RL1N .& NILSSON5. I n other forms of spontaneous bleeding in patients suffering from severe hemophilia, no definite effect of E A C A could be demonstratedlS, zs, '~~ I n April 1969, AB Kabi presented Cyklokapron | (tranexamic acid, AMCA) which has approximately a ten times more powerful anfifibrinolytic activity than Epsikapron. The side effects are also reported to be less for Cyklokapron than for Epsikapron. Local hemostatic treatment of the extraction alveolus, combined with suture and the use of acrylic splints as protection for the coagulum in the alveolus, with or without substitution therapy, have been used as a local means of assistance over a period of years1%14,~4, 41. I n several of these studies fibrinolytic inhibitors also have been used. PIZZONI, CORTELLARO ,• MANNUCC131 have made a comparative study with and without local treatment of the alveolus using both singIe dose and intermittent substitution therapy. Other authors have not availed themselves of local means of assistanceS,ls,'14. The costs for tooth extraction in hemophiliac patients are high, not only regarding the substitution treatment, but also for the medical service. The study here presented is intended to illustrate various ways of decreasing the risks and complications, thus reducing not only the infusion quantity but also the number of days lost through tooth extraction in patients suffering from different forms of coagulation disorders.
Material and methods The clinical material comprised 67 patients treated at the Department of Oral and Jaw Diseases at the Karolinska Sjukhuset during 1965-1973. Sixty-four of these patients were already suffering from known coagulation defects at the time of the first extraction. The material also included three patients whose coagulopathy was diagnosed under the treatment in question, due to postextraction bleedings of long duration. The distribution of the patient material as to the different coagulation diseases, and sex and age, is given in Table 2. In addition to the above mentioned patients, there were four with rare coagulation defects. These four are commented upon separately. A total of 264 teeth and root stumps were extracted, including enucleating a radicular cyst and performing a preprosthetic operation. In 16 of the operations it was necessary to prepare a mucoperiosteal flap and thesehave therefore been captioned as operation (op). The extractions and operations have been performed in 118 treatment sessions. One treatment session is defined as the period of time from the start of treatment, usually the day prior to extraction, or in some cases the extraction day, until no bleeding has occurred for 3-5 days. Generally, this means for Group 1 and 2 the day the patient is discharged from hospital. In the treatment session where two or more teeth were extracted, this has often been perTable 2. Patient distribution in coagulation disorders, sex and age Disease Hemophilia A severe moderate mild Hemophilia B severe (1.4 %) mild v. Willebrand's disease severe mild Total
No. of patients
M
F
Age range
15 9 18
15 9 14
0 0 4
15-51 20-62 9-56
6 4
6 3
0 1
28-48 8-57
2 13
0 2
2 11
29-31 4-81
67
49
18
4-81
T O O T H E X T R A C T I O N S IN H E M O P H I L I A C S t a b l e 3. Patient distribution in the different groups and treated in more than one group
indicating the
No. of patients
Total
number
1
2
3
No. of patients
3 7 9
11 2 8
6 2 7
15 9 18
2 1 4
2 3
3 1
4 1
6 4
1 1
7
2 3
7
2 13
2
1
31
30
27
67
11
3
formed on two or more extraction occasions. One treatment session can thus include one or more extraction occasions (see Figs. 1-3). In all cases except one, where intubation anesthesia was used, the extractions and/or operations were carried out under local anesthesia (Xylocain| 2 %). In n o case did a demonstrable h e m a t o m a appear after the injections. T h e grouping given below can be traced to changes in the methods of treatment. In Group 1, only substitution therapy was used. T h e patients were treated in this m a n n e r during 19651969. Group 2 consists of patients treated with infusion therapy, supported by fibrinolytic inhibitors and antibiotics. This took place during 1969-1971. In G r o u p 3, the G r o u p 2 treatment was supported by local hemostatie means in the extraction alveolus and an acrylic splint attached to the surrounding teeth iu order to protect the coagulum in the alveolus. F o r the majority of patients in Group 1, and all the patients in Groups 2 and 3, a treatment schedule was prepared before the patient was admitted to hospital for extraction. This schedu[e took into consideration t h e degree of severity of the illness and the experience gained from previous treatment. A more detailed account of the treatment principles for the different groups is given below. The distribution of the patients with different coagulation disorders between the three groups is given in Table 3.
of patients
No. of patients in combinations
Groups
Hemophilia A severe moderate mild Hemophilia B severe (1.4 %) mild v. Willebrand's disease severe mild
5
1+2
1+3
2+3
1 1
2
1+2+3
2 1
1
1 5
2
G R O U P 1. S U B S T I T U T I O N T H E R A P Y The patient was admitted to hospital the day before the tooth extraction. Patients suffering from hemophilia A and B received substitution therapy with plasma or factor concentrate immediately before the extraction was performed. The infused quantity for patients with hemophilia A was calculated so that the patient's factor level would rise to 30-50 % of the normal value. The next 2-3 days following the extraction the level was permitted tc~ fall to 25-30 %, and kept at about half this value for 6-10 days. For patients with hemophilia B there was n o Swedish factor concentrate available during the first years, which is why only substitution treatment with plasma could be offered. In consideration of the risk of hypervolemia, the level in these patients on the day of extraction could not b e raised to more t h a n 10-20. The patient was discharged from hospital when he had b e e n free f r o m bleeding, without substitution treatment, for 3-5 days. In patients suffering f r o m yon Willebrand's disease, the substitution treatment was begun the day before the extraction, as these patients show also a slower secondary factor rise, in addition to the primary rise. On several occasions postoperative bleedings of long duration occurred in this group, which necessitated renewed substitution treatment. In some of these cases the "old" bleeding coagulure was removed u n d e r local anesthesia. The
RAMSTR~3M A N D B L O M B * C K alveolus was plugged with Spongostan| and the t a m p o n r e t a i n e d in position by suturing. On the few occasions w h e n severe postoperative infections occurred, penicillin was administered. G R O U P 2. S U B S T I T U T I O N T H E R A P Y SUPPORTED BY FIBRINOLYTIC INHIBITOR AND ANTIBIOTICS All t h e patients in this group were routinely ti'eated with Cyklokapron and penicillin. No p a t i e n t in this group was f o u n d to be oversensitive to penicillin. The treatment with Cykl o k a p r o n a n d penicillin was begun the day bef o r e the extraction, as a rule on the same day as the patient was admitted to hospital. The quantity of plasma and/or factor concentrate was calculated a n d administered during the extraction day, in accordance with what has b e e n said above for Group 1. T h e factor content in the following phase was, however, kept at a lower level a n d the treatment concluded earlier. I n m a n y patients, though, the factor level was raised o n the extraction day only to 20-30 % (in G r o u p 1 30-30 %). This applies m a i n l y to patients treated during the latter haIf of 1970, and 1971, as the experience gained f r o m the c o m b i n e d method of substitution therapy, fibrinolytic inhibitors and antibiotics was considered to justify also an initial lowering of the level. G R O U P 3. S U B S T I T U T I O N T H E R A P Y SUPPORTED BY FIBRINOLYTIC ~ INHIBITOR, ANTIBIOTICS, LOCAL TREATMENT OF ALVEOLUS AND ACRYLIC SPLINT Fibrinolytic i n h i b i t o r and antibiotics were administered as in G r o u p 2. Six patients on 13 extraction occasions were n o t given penicillin, however. One o f those patients reported an oversensitivity to penicillin. In the remaining cases, the risk of infectious complications in extraction was assessed as minimal so the administration of penicillin was n o t considered indicated. Cyklokapron was given perorally, b u t in two of t h e cases intravenously. The quantity of factor concentrate given o n the extraction occasion was calculated as increasing t h e patient's f a c t o r level to 5-10 % of the norm a l value. O n the day a f t e r the extraction either the s a m e quantity was given, or half or none at all, depending u p o n previous experience of the
patient's - or corresponding patient's - respective response to treatment. Immediately prior to the extraction a n alginote impression was taken of the jaw where the tooth to b e extracted was situated. On the plaster cast then made, the or those extraction teeth in question were erased, a n d an acrylic splint of the omnivac type was made. The splint was shaped so that it also covered 3-4 m m of the alveolar process. The tooth was then extracted with as little t r a u m a as possible and the alveolus filled with T h r o m b a s e 500| and T h r o m b a s e dentaire| A piece of Surgicel| was then placed over the alveolus as a shield. The completed acrylic splint was attached to the surrounding teeth with phosphate cement. T h e acrylic splint remained in place for 8-10 days. It should b e pointed out that this acrylic splint must be so shaped that it does not cause decubitus in the surrounding tissues. The first four patients in 1972 were treated with an acrylic splint directly polymerized on t h e teeth 41. This was shaped manually in Paladur| before the tooth extraction. After extraction, Palavit| was applied to improve the fit against the alveolus. However, these splints were very clumsy, so future splints were made according to the omnivac method. P R E P A R A T I O N S A N D H E M O S T A T I C AIDS Blood
Blood transfusions were used on only two occasions, w h e n it was necessary to compensate for blood loss. Plasma Fresh frozen plasma -
Plasma was prepared as rapidly as possible from fresh drawn blood and thereafter frozen at -20 ~, at the latest within 3--4 h o u r s after drawing. (Due to storage problems the adequate t e m p e r a t u r e for maintaining the activity, --40 ~ t o - 7 0 ~, was not used.) It was stored for 2-3 months. Consideration was paid to the blood group of the patient. Factor concentrate Factor VIII concentrate
- A H F concentrate from AB K a b i containing 2-3 units of F a c t o r V I I I a c t i v i t y p e r m l . T h e c o n c e n t r a t e was, as a rule, given with respect to A B e compatibility.
c o n c e n t r a t e - PPSB from Centre National de Transfusion Sanguine, Paris, containing 25 units of F a c t o r I X p e r ml. Factor IX
T O O T H E X T R A C T I O N S IN H E M O P H I L I A C S Preconativ| AB Kabi, containing 25 units of Factor IX per ml.
Fibrinolytic inhibitors Cyklokapron| AB Kabi, aminomethylcyclohexane-carboxylic acid (in Sweden called AMCA). Tablets of 0.5 g have been used in a dosage of 2 tablets 3 times daily. When given intravenously the dosage has been 10 ml at 0.1 g/ml 3 times daily. Analgesics V-penicillin (Calciopen-K| Leo). Tablets of 0.4 g were used. 1.6 g was given daily. Analgesics The only preparation the patients were allowed to use was Alvedon| (Draco). This preparation contains 0.5 g paracetamol per tablet. On some occasions, preparations containing acetyl salicylic acid and some other less suitable preparations have been given inadvertently. Local hemostatics 1. Surgicel| oxidized cellulose preparation from Johnson & Johnson, U.S.A. 2. Spongostan| AB Ferrosan. 3. Thrombase 500| freeze-dried powder containing 500 units of thrombin per bottle, Laboratories de I'ISH, Paris. 4. Thrombase dentaire| bottle containing 2 small sponges, containing total of 100 units of thrombin, Laboratories de I'ISH, Paris. Acrylic splints Paladur| Palavit| and splints prepared according to the omnivac method. C A L C U L A T I O N OF A P P R O P R I A T E AND ADMINISTERED INFUSION QUANTITY During every treatment session the infusion quantity administered and any occurrence of postoperative bleeding have been recorded daily (Figs. 1-3). The assessment of bleedings in all cases has been made by the author (G.R.), with the exception of two daring 1965. For calculation of the requisite factor level, for the extraction occasion, the quantity of factor concentrate or plasma has been counted in units (U). One U has here been defined as the quantity of the coagulation factor present in I ml of fresh plasma. Thus, a patient with severe hemophilia A having a plasma volume of 2,500 ml needs the administration of 500 U
of Factor VIII in order to raise the F a c t o r VIII concentration to 20 (i.e. 0.2 U of Factor VIII per ml plasma). The plasma v o l u m e of the patient has been calculated according to the formula by INIO.EY,BROOKS & Ke~UO~R~0, corrected for hematocrit: (668 + (30 + wt in kg) • (100 -- hematocrit) 1 0 0 - 47 (normal hematocrit) This formula has proved to be satisfactory in the treatment of children and adults ( M . BLOMB~CK,personal communication). Evaluation of the patient's expected plasma factor level on transfusion of a certain quantity of plasma is relatively uncertain as pointed out by BmQs & MACFARLANE1. In tooth extraction in patients with severe hemophilia A, these authors administered plasma to six of the patients. The measured mean value of the factor increase was only 71% of that expected (the highest value being 87 % and the lowest 62 %). The difficulties in obtaining absolutely fresh plasma are great, and we therefore used freshfrozen plasma. The content of the factors contained in the plasma, especially Factor VIII, decreases rapidlyO both at preparation and at storage of plasma at temperatures above --30 ~ to --40 ~. The content of Factor VIII can thus have decreased to 30-70 % of the original value as the plasma was stored under unsuitable conditions. Uncertainty in evaluation has therefore been judged to be great. In the cases where evaluation of the expected factor increase at plasma transfusion was undertaken, the plasma content of Factor VIII was taken to be 0.5 U per ml plasma. The in vitro activity and stability for Factor IX in fresh-frozen plasma is higher than for Factor VIII. The activity for Factor IX has here been evaluated at 0.75 U per ml plasma. The in vivo yield from the quantity of Factor IX administered is, however, considerably lower than in the administration of Factor V I I I and has therefore been evaluated at about one-third zT. The quantity which the patient received (300400 ml pre- and 300-400 ml immediately postoperatively) was based on our previous experience in tooth extraction. Particularly in those patients with yon Willebrand's disease, uncertainty in the evaluation of the factor rise following the administration of plasma is considerable. In these patients there is, in addition to the immediate Factor VIII rise, a secondary rise. Also, the vascular
8
R A M S T R O M A N D BLOMB.~CK
Table 4. D i f f e r e n c e in substitution therapy and hospitalization days in different groups
Disease
Hemophilia A severe < 1% VIII
Hemophilia A moderate 1--4 % V I I I
Hemophilia A mild > 5 % VIII
v. Willebrand's disease
No. of No. of ex. G r o u p patients tracted teeth
1
3
6
2
11
26
3
6
12
1
7
37
2
2
18
3
2
5
1
9
31
2
8
22
3
8
20
1
7
25
2
5
12
3
7
18
Hospitalization days
AHF ml
Total: Per tooth: Total: Per tooth: Total: Per tooth:
45 7.5 95 3.7 32 2.6
6,300 1,050 15,600 600 2,100 175
7,600 1,260 4,800 185 0 0
19,550 3,260 41,400 1,592 5,250 438
Total: P e r tooth: Total: Per tooth: Total: Per tooth:
11 3 29 1.6 3 0.6
3,200 86 2,800 156 200 40
56,100 1,516 2,400 133 0 0
36,050 974 8,200 456 500 100
Total: Per tooth: Total: Per tooth: Total: Per tooth:
92 3 17 0.8 3 -
1,700 55 700 32 0 0
41,200 1,330 600 27 0 0
24,850 802 2,050 93 0 0
Total: Per tooth: Total: Per tooth: Total: Per tooth:
70 2.8 24 2 0 0
1,500 60 900 75 0 0
29,400 1,176 6,250 520 0 0
18,450 738 5,375 475 0 0
Plasma No. of ml units*
Fact. IX conc.
Hemophilia B <~ 1.4 % I X
Hemophilia B > 2 % IX
* I n v i t r o value
1
2
3
2
3
7
3
4
6
1
3
8
2
1
2
3
1
3
Total: P e r tooth: Total: Per tooth: Total: Per tooth:
27 9 34 4.9 21 3.5
200 67 160 23 120 20
10,800 3,600 9,800 1,400 0 0
13,100 4,366 11,350 1,621 3,000 500
Total: Per tooth: Total: Per tooth: Total: Per tooth:
27 3.4 8 4 0 0
0 0 0 0 0 0
15,450 1,930 1,000 500 0 0
11,690 1,460 750 375 0 0
TOOTH EXTRACTIONS IN HEMOPHILIACS effect of the bleeding time factor cannot be assessed as there is no acceptable determination method for this particular factor. The determination of the bleeding time according to Duke was performed in some of the cases to confirm that the patient had a satisfactory vascular hemostatis~-~. In the treatment of patients with yon Willebrand's disease, transfusion treatment was, as mentioned, often begun the day prior to the tooth extraction in order to exploit the secondary Factor VIII riseL Before and precisely half-an-hour after completed treatment, samples were taken for analysis of the patient's plasma factor level. It has previously been shown that this particular time was best for the measurement of an optimal level (hemophilia A and B)8. The half-life for Factor VIII has been evaluated to be about 9-18 hours, and for Factor IX 18-40 hours~7.
different groups is shown in Table 4. A s has previously been pointed out, a changeover from plasma and/or factor concentrate therapy in Group 1 and 2 to only factor concentrate in Group 3 took place. I n order to reach an approximate assessment of the quantity of substitution therapy per tooth in the different groups, an evaluation of the in vitro number of units (U) was made. As shown in Table 4, the quantity of preparations for the severe hemophilia A cases decreased from 3260 U/tooth in Group I to 1660 U/tooth in Group 2 and to 440 U / t o o t h in Group 3. The number of days in hospital was correspondingly reduced. A good comparison between the treatment results is reflected also in the patient examples given in Figs. 1-3. A summary of the number of bleeding complications in the different groups is given in Table 5. In Group 1, postoperative bleedings occurred in 59 % of the treatment ses-
Results A summary of the substitution quantity and of the number of days in hospital for the
,.~ 20 x z
16
i-~
IO
B.B, As EXTRACTION JUNE" JULY 196g IGROUP 21
~O0O a
J FACTOR CONCENTRATE
900 = t PtAS.A
6OO
~d
5
27
30 '~ zs
9 NEASURED FACTOR-LEVEL
&DO ~
28
29
30
,, ill Jilt11 I
2
:1
S
&
6
?
9
+ BLEEDING Z00
DATE
M.L. A M EXTRACTION NOV. 1969 (GROUP 2) IEXe_LI LExLL~.
EXTRACTION JAoN.1970 (GROUP 2)
IEXI~
20
ixUL~ [EXZ_!I
9
>
F EDD .~
5
~
"/
I I 8
9
10
II
12
tll 13
I&
15
IIS
I?
10
/
,, /
I&
IS
t6
17
16
Ig DATE
Fig. 1. A8 means hemophilia A severe form, A~o means hemophilia A moderate form, ML see also Table 6. For explanation of preparations and units infused, see p. 7.
RAMSTR~3M A N D BLOMB~_CK
10
U.H. AMo EXTRACTION JAN. 1969 (GROUP 1 ) .., < X
25
~= zo
$ /,00
z
.J tu
r,
m
,,=
I I :i
s 10
30
II
12
t3
+
I/.
§
tS
lS
17
18
~
10
§
20
§
11
22
2~1
2&
DATE
P.O,S. B s OPERATION MARCH-APRILlgBg (GROUP 11
[Ex~
. , 2S ,4 Z *~o 20 z
o~
ig
s00
is
_z
600
d
,,', 10
x S
13
1/,
lS
16
17
16
19
4
20
"2.1 §
22 +
23 9
24 +
2S
26
2'7
§
28
29
30
31
1
2
DATE
§
Fig. 2. A~[O m e a n s hemophilia A moderate form. Bs means hemophilia B severe form. F o r explanation of preparation and units infused, see p. 7.
Table 5. Bleeding complications in different groups and diseases
Disease
Memophilia A severe 9m o d e r a t e mild Memophilia B severe mild v. Willebrand's disease Total
Group No. of treatm, session
1 No. of bleeding compl.
Group 2 No. of No. of treatm, bleeding session compl,
Group. No. of treatm, session
3 No. of bleeding compl.
3 9 11
3 7 8
13 3 9
5 0 4
6 2 11
2 0 1
2 2 12
2 1 2
3 2 6
0 0 1
5 3 13
1 0 0
39
23
36
10
40
4
TOOTH EXTRACTIONS IN HEMOPHILIACS 2O
o~ t5
B.S. A s EXTRACTION 2o. R,S.A s EXTRACTION 20, G.T.H,As EXTRACTION MARCH 1972 (GROUP31 MARCH19721GROUP3) APRIL 1972 {GROUP 3) [ExlJ~ 1~
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K.G.J, Ps EXTRACTION 20 - S.L. Bs EXTRACTION JAN.t972 (GROUP 3) OCT. 1973 (GROUP 3 ) [Ex L~ ,s ,?,
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Fig. 3. AS means hemophilia A severe form. BS means hemophilia B severe form. For explanation of preparation and units infused, see p. 7.
sions. In Group 2, the Needing frequency decreased to 28 %, and in Group 3 it was reduced to 10 %. It should also be pointed out that the bleedings in Group 1 were far more frequent and prolonged than those o c c u r r i n g ' i n Groups 2 and 3. Nine of the bleedings in Group 1 were described as severe and prolonged, but in Groups 2 and 3 there was no such bleeding. Patients with moderate forms of hemophilia A were found to be relatively difficult to treat according to the method used for G r o u p 1. M a n y of the postoperative bleedings registered were particularly prolonged and complicated. This patient category responded very well to Cyklokapron and antibiotic therapy and no bleedings were registered in G r o u p 2. Several patients with miId forms and even m o d e r a t e forms of hemophilia and mild forms of votz Willebrand's disease could be treated as outpatients when changed over to treatment according to G r o u p 2,
and later to Group 3. This has lightened the hospital's burden considerably. Extractions have also been performed on patients with rare coagulation defects. T w o patients with a mild Factor X deficiency and two patients with a m i l d F a c t o r X I deficiency have thus been treated. T h e patients were first given large quantities of plasma. Later, following the administration of fibrinolytic inhibitors and antibiotics, the plasma treatment could be discontinued. One p a tient developed hepatitits after plasma treatment in 1967.
Discussion The main causes of bleeding in tooth extraction in patients with coagulation defects are alleged to be (1) too low a level of the lacking coagulation factor, (2) local fibrinolysis and (3) traumatic injury to the coagulum formed.
12
RAMSTROM AND BLOMB,~CK
In Group 1, where only substitution therapy was applied, the factor level in several cases was in all certainty too low to give a good coagulum. T h e bleedings often started within the first 24 hours following the extraction. In those cases in which the factor level was acceptable from the hemostatic point of view, several of the postoperative bIeedings were probably caused by local fibrinolysis4dl,etk I n these patients the bleedings often began 3-5 days after the extractions. W h e n substitution therapy was instituted, as in Group 1, with a calculated initial factor level of 30-50 % and subsequently 15-30 % during 2-3 days after the extraction, this level clearly proved too low if at the same time there seemed to be local fibrinolysis and severe infection in the alveolus. It must be remembered that, generally, the indication for tooth extraction in patients with_ various coagulation defects is most usually teeth gravely affected by caries and osteitis. (In one of the cases reported in this study, there were orthodontic indications for extraction.) Whether or not the primary infection increased, the fibrinolytic activity cannot be established with any degree of certainty, as no such laboratory examinations took place. It is quite possible that when the coagulum disintegrates owing to local fibrinolysis, the all too low factor level does not suffice for the formation of a n e w coagulum, and diffuse bleeding ensues. When a new transfusion was given, the factor level rose, a new coagulum was formed a n d the bleeding ceased. In some of the cases in Group 1 this occurred 3-5 times before a healing of the alveolus was attained. It is known to be very important that the patient does not begin to bleed, as this entails an increased consumption, and hence a more rapid drain of the faetor administered. In order to stop the postoperative bleedings, 14 of the patients in Group 1 were treated by plugging with absorbable go-
latinous sponge (Spongostan), and suturing. In eight of these cases, plugging took place without antibiotic protection. T h e result in all of these cases was a violent swelling at the operation site and a rapid rejection of the plug. In all probability, this was caused by. an infection encapsulated in the alveolus by the hemostatic plug, and the consequent action of the foreign body resulted in the rejection of the pIug. In those cases in which antibiotics were administered, however, this tendency towards rejection was not seen. Thus, clinically, we have observed a good local effect of the antibiotic therapy in six of the cases in Group 1. These locally observed clinical advantages in the antibiotic treatment of patients with different bleeding diseases were the reason for the routine use of penicillin with the introduction of fibrinolytic inhibitors in April 1969. There is reason to believe that the antibiotic therapy initially protected against infection, thus probably decreasing the local fibrinolyric action. However, there are still no examinations confirming that this Iocal fibrinolysis would be decreased by the use of antibiotics. That this local fibrinolysis played a large part in subsequent bleedings is shown by the favorable results following the introdudtion of fibrinolytic inhibitors and antibiotics in Group 2. Thanks to these preparations the quantities of the infusions and the number of days in hospital could be considerably reduced. The postoperative bleedings, very worrisome and irritating to the patient, decreased manifestly upon the change to treatment according to Group 2. This also implies a considerable saving of labor for the staff of the department where the patient is hospitalized. These good results achieved in changing from treatment according to the method in Group 1 to the method in Group 2 included decreased risk of complications and reduced substitution quantities and number of days
TOOTH EXTRACTIONS IN HEMOPHILIACS in hospital. Several authors, as has previously been pointed out, have reported good results with local treatment of the alveolus combined with acrylic splints. It has also been possible to undertake tooth extraction according to these methods in patients with circulating anticoagulants41. In an attempt to further minimize the complication risks in tooth extraction, it was decided to try treating the alveolus locally and using acrylic splints to protect the coagulum in the alveolus. As seen from Table 4, there was a decided improvement in the treatment results when the previous general methods of treatment were complemented with local methods. The reasons for these improved results when changing from the treatment method of Group 2 to that of Group 3 are probably several. The coagulum formed in the alveolus was well embedded in an absorbable gelatinous sponge (Thrombase dentaire). Thrombine powder (Thrombase 500) gave a quicker and more stable coagulation. The task of the well-attached acrylic splint should at least have been two-fold. SCHULTE & W/SRNER 86 demonstrated a deteriorated coagulum formation on contact between blood and saliva. Acrylic splints have been able to reduce considerably both this unfavorable effect of the saliva flow and also the risk of traumatic injury to the coagulum. A direct evaluation of the different parts of this local hemostatic supporting treatment is, however, difficult. In patients with severe and moderate forms of coagulation disorders, however, local alveolar treatment and the use of an acrylic splint seem to be necessary if the factor level is to be kept low, even when penicillin and Cyklokapron are administered. In patients with the mild forms, the supporting local treatment is not generally necessary because the fibrinolytic inhibiting effect of Cyklokapron, possibly combined with antibiotics, is sufficient. It has been proved by experience that it is
13
possible to extract several teeth on one extraction occasion, provided that a sufficient number of teeth remain for the atfixation of the acrylic splint. Comparing the treatment results for patients treated by different methods on separate extraction occasions, many interesting observations can be made (Table 6 and Figs. 1-3). RA was treated as a Group 1 patient in 1968, then receiving a total of ca. 4,100 U. On extraction 1 year later in Group 2, he received 1,700 U, this time with reduced postoperative bleeding. AJ in 1967 received as a Group 1 patient 3,000 U in the form of plasma. The extraction 3 years later as a Group 2 patient necessitated ca. 1,000 U, and as a Group 3 patient in 1972 only 500 U. Observations of the factor level at the time of extraction show that this can be kept considerably lower than the 40 % suggested by BJORLIN.& NILSSON8 and still give entirely acceptable hemostasis: without postoperative bleeding. In the five extraction sessions of severe hemophilia B patients, the factor level was calculated to lie between 5 and 10 %. Here, only one patient showed an insignificant postoperative bleeding, probably due to a factor level of 0.2 % on the extraction occasion (suspected case of circulating anticoagulants). This all too low factor level in all certainty did not give an adequate coagulum, which may have been the cause of the postoperative bleeding. This bleeding stopped nicely, though, upon the intravenous administration of Cyklokapron only. LUCAS, CAKROL, FINKELMAN ,~; TOCANTINS 2:2 a n d LUCAS, FINKELMAN ,~,~ TOCANTINS2~ used hypnosis in tooth extraction with good results in patients with coagulation defects. Here it is of the utmost importance that the patient is calm and has confidence in the physician and dentist treating him. Therefore, patients who are anxious and nervous concerning the postoperative
RAMSTROM AND BLOMBXCK
14
Table 6. T o o t h extractions performed in the same patient in different groups (1, 2 a n d Patients are g r o u p e d for comparison purposes Patient's initials RH GTH RA RS BS ML
Disorder Hemophilia severe Hemophilia severe Hemophilia severe Hemophilia severe Hemophilia severe
A A A A A
Hemophilia A moderate
RGJ
Hemophilia A moderate
GTo
Hemophilia mild Hemophilia mild Hemophilia mild Hemophilia mild
WL GTe NB
YJ
AJ
KGJ
A A A A
Hemophilia A mild Hemophilia B severe
Hemophilia B severe
AR
y o n Willebrand's disease mild
ACJ
yon Willebrand's disease mild
MB
y o n Willebrand's disease mild
No. of extracted teeth
Hospitalization days
3 6 2 4 1 1 2 1 4 1
27 15 6 15 12 I0 8 5 9 4
12,000
5 11 5 1 4 op
10 15 7 4 3
4,200
1 1 1 1 2 12 1 1 op 2 1 1 1
0 0 2 0 10 13 3 0 0 1 0 0
2 1 1 1 2 2 1
No. of units infused Gr. 1
Gr. 2
Gr. 3
3,750 2,200 1,000 4,150 1,750 2,500 250 3,000 750 4,500 2,250 1,200 500 250 400 1,050 1,250 800 0 0 0
8 6 5 3 3+3 8 6
3,000
1 op 2 1 1 1 2 1 1 1
8 11 2 2 2 2 0 5 2
3,000 3,050
i op 1 op 1 op
3 0 0 0
1 op
3).
1,700 1,000 500 500 3,250 1,000
300
150 350 200 800 400
TOOTH EXTRACTIONS IN HEMOPHILIACS course should be retained in hospital for an extra day or two. It is also of the utmost importance that patients with coagulation defects, at least in severe and moderate cases, are familiar with the physician and dentist treating them. It is well known that a satisfactory platelet function including platelet aggregation, is necessary both for the primary hemostasis and for the activation of the coagulation mechanism. Blocked platelet aggregation is to b e observed after treatment with acetyl salicylic acid, and also after certain other medicaments (phenylbutazon, indomethazin)m. It is thus very important to avoid such medicaments in order to achieve a quick primary hemostasis and stable coagulurn. The Department staff was instructed to administer no painkiller other than Alvedon| (paracetamol). Despite this, by an oversight nine patients received medicaments containing acetyl salicylic acid. The five postoperative bleedings which occurred in these nine patients can have been caused, or at least aggravated, by the decreased platelet aggregation. T w o of the three patients whose coagulopathy was revealed by bleeding after tooth extraction had, on the extraction occasion in question, used preparations containing acetyl salicylic acid. Concerning patients with a severe form of y o n Willebrand's disease, our experience, as shown by the tables, is little. However, it would seem desirable, even though local hemostatics and the acrylic splint are used, to use sufficient substitution therapy to normalize the bleeding time ( ~ 7 rain accord]ng to Duke).
Acknowledgments - The authors wish to express their sincere gratitude to professors
OUNNAR M~TENSSON, CARL-AxELHAMBEROER and Ar~ NO~DBNRAM for valuable help and inspiring discussions and to Mrs. ULLA WALLINDER for valuable assistance.
15
References 1. Bioos, R. & MACFARLaNE, R. G.: Treatment o] haemophilla and other coagulation disordelw. BlackwelI Scientific Publ., Oxford 1966, p. 144-3.65 and 250-261. 2. BJOaLIN, G. & NILSSON, I. M.: Oral surgery in patients with coagulopathies. Acta Odontol. Scan& 1963: 21: 99-139. 3. BJORLIN, G. & NtLSSON, I. M.: Oral surgery in patients with coagulopathies. If. Odontol. Revy 1965: 16: 216-237. 4. BJ~SRLIN,13. & NILSSON, I. M.: Fibrinolytic activity in alveoli after tooth extraction. OdontoL Revy 1968: 19: 197-204. 5. BJORLIN, G. &NmssoN, I. M.: Oralkirurglska ingrepp p~t patienter reed koagulopatier. III. Sven. Tandlaek. Tidskr. 1972: 65: 431-440. 6. BLOM~XCK, M.: Purification of antihemophilic globulin. I. Some studies on the stability of the antihemophilic globulin activity in fraction 1-0 and a method for its partial separation from fibrinogen. Arkiv Kemi 1958: 12: 387-396, 7. BLOMBACK, M., BLOMItXCK, B. & NILSSON, I. M.: Response to fractions in yon Witlebrand's disease. In: BI~INX_~OtJS,K. M. (ed.): The hemophilias. Univ. North Carolina Press, Chapel Hill 1964, p, 286-294. 8. BLOMBACK, M. & NILSSON,I. M,: Treatment of hemophilia A with human antihemophilic globulin. Acta Med. Scand. 1958: 161: 1-2,1. 9. BLOMBACK, M. & RAMSTROM, G.: B15darsjuka reed hiinsyn speciellt till odontologiska problem. Tandlaekartidningen 1971: 63: 449-455. 10. BUCHANAN, J. C. & LEAVELL,B. S.: Pseudohemophilia: Report of 13 new eases and statistical review of previously reported cases. Ann. Intern. Med. 1956: ~14:241-256. 11. BUMP, R. L, & KOLODNY, S. C.: Fibrinolysis: A possible factor in the control of postoperative hemorrhage in the patient with hemophilia. Oral Surg. 1973: 36: 195200. 12, FINDLAY~ I. A. & NICHOLL~ B.: Tooth extraction in patients with hemophilia. Oral Surg. 1960: 13: 1167-1180. 13. FLUUR, E., NYLEN, B. & ZETTERQVIST, E.: Kirurgi inom huvudhalsregionen hos bl~5dare. Laekartidningen 1966: 63: 1045-1053. 14. GEORGE, W. A.: Prosthetic splints as an aid in the treatment of hemophilia. J. Prosthet. Dent. 1961: 11: 987-989.
16
RAMSTRt3M AND BLOMB.KCK
15. GIORDANO, N. D., WATKINS, R. S., RAmVOYVITCH, M. O., GooDsrrr, E.: Dental extractions in hemophilic patients on aminocaproic acid prophylaxis. Oral Surg. 1968: 26: 160-166. 16. GLOGOFF, M., BAUM, S. M., SUSSMAN, R., STEWART, S. & STOOVACK,J. C.: Management of the hemophilic oral surgery patient, I. Oral Surg. 1972: 30: 252-262. 17. I--IAXmERO,L., RAMOILEN, O. t~ TENGBERG, J.-E.: Nya erfarenheter i samband reed tandextraktioner p~ blSdare. Sven. Tandlaek. Tidskr. 1959: 52: 293-299. 18. H&YTON-u D. S.: Oral surgery on the haemophilic patient. In: WALTER, R. V. (ed.): Trans. Congr. Int. Assoc. Oral Sarg. 1970, p. 496-499. 19. I_~ogaM, G. I. C.: Dental care in haemophilia. T h r o m b . Diath. Haemorrh. 1971: Suppl. 43: 213-218. 20. INKLEY, S. R,, BROOKS, L. & KREUGER,H.: A study of methods :for the prediction of plasma volume. J. Lab. Clin. Med. 1955: 45: 841-850. 21. KANESHIRO, M. M., MIELKE, C. H. Jr., KASI'ER, C. K. & RhPAI~ORT, S. J.: Bleeding time after aspirin in disorders of intrinsic clotting. N e w Engl. J. Med. 1969: 281: 1039-1042. 22. LOCAS, O. N., CARROL, R. T., FINKELMAN, A. & TOCANTrNS, L. M.: Tooth extractions in hemophilia. Control of bleeding without use of blood, plasma or plasma fractions. T h r o m b . Diath. Haemorrh. 1962: 8: 209220. 23. LUCAS, O. N., FINKELMAN,A. &TOCANTINS, L. M.: Management of tooth extractions in hemophiliacs by the combined use of hypnotic suggestion, protective splints and packing of sockets. J. Oral Surg. 1962: 20: 488-500. 24. MCINTYRE, H.: Dental extractions in patients with hemophilia syndrome. Oral Surg. 1965: 19: 163-173. 25. McMrLLAN, C. W , WEBSTER, W. P., RoaERTS, H. R. & BLYTnE, W. B.: Continuous intravenous infusion of factor VIII in classic haemophilia. Br. J. HaematoI. 1970: 18: 659-667. 26. MEOQUmR, R. J.: Fibrinolytic activity in human dental sockets after extractions, J. Oral Surg. 1971: 29: 321-328. 27. NILSSON, I. M.: Bl6dnlngs- och tromboss#tkdomar. AB Kabi, Atmqvist & Wiksell, Stockholm 1971.
28. NILSSON, I. M. & BJORKMAN, S. E.: Clinical experiences with e-aminoeaproic acid (~ACA) as an antifibrinolytic agent. Acta Med. Scand. 1961: 170: 487-509. 29. NILsso~, I. M. & BLOMBXCK, M.: yon Willebrand's disease in Sweden - occurrence, pathogenesis and treatment. Thromb. Diath. Haemorrh. 1963: 9: Suppl. 2: 103-118. 30. NILSSON, I, M., BLOMB.~CK, M. & RAMOREN, O.: Haemophilia in Sweden. VI. Treatment of haemophilia A with the human antihaemophilic factor preparation (Fraction 1-0). Acta Med. Scand. 1962: Suppl. 379: 61-110. 31. PIZZONI, D., CORTELLARO, M. t~ MANNUCCI P.M.: Replacement therapy and local measures for dentat extractions in haemophiliacs: a comparison of various schemes of treatment. VIIth. Congr. Wld. Fed. Haemophilia. Teheran 1971. Excerpta Med. 1973: 252: 242-244. 32. RAMGREN, O.: Haemophilia in Sweden. III. Symptomatology with special reference to differences between haemophilia A and B. Acta M e d . Scand. 1952: 171: 237-242. 33. REID, W. O., LUCAS, O. N., ~,ANSISCO, J., GEISL~R, P. H. & ERSL~V, A. J.: The use of epsilon-aminocaproic acid in the management of dental extractions in the hemophiliac. Ant. J. Med. Sci. 1964: 84: 184188. 34. ROKICKA-MILF.,WSKA, R., KRAJEWSKA-MARTEL, A. & DVSZY-LAunE, B.: Application of epsilon-aminocaproic acid for oral mucosal bleedings in haemophiliacs. Pol. Arch. M e d . W e w n . 1966: 4/10: 445. 35. RUBIN, B., LEVINE, ]3. 8z ROSENTHAL, M. C.: Complete dental care of the hemophiliac. Oral Surg. 1959: 12: 665-675. 36. SCHm-TE, W. & W6RNER, H.: Speicheieinfltisse auf die Blutgerinnung bei hS_morrhagischen Diathesen - thromboelastographische Untersuehungen. Dtsch. Z a h n aerztl. Z. 1968: 23: 835-843. 37. StLWER, J.: yon Willebrand's disease in Sweden. A c t a Paedialr. Scand. 1973: Suppl, 238. 38. SINCLAIR, J. H.: Current concepts in the dental treatment of haemophiliacs. T h r o m b . Diath. Haemorrh. 1971: Suppl. 43: 203-212. 39. SKOELD, E.: On haemophilia in Sweden and its treatment by blood transfusion. Acta M e d . Scand. 1944: 117: Suppl. 150: 165.
TOOTH EXTRACTIONS IN HEMOPHILIACS 40. STRAUSS, H. S., KEVY, S. V. & DIAMOND, L. K.: Ineffectiveness of prophylactic epsiIon aminocaproic acid in severe hemophilia. New Engl. J. Med. 1965: 273: 301304. 41. SZeIRGLAS,H.: L'h6mostase locale dansles extractions dentaires chez l'h6mophile. Thromb. Diath. Haemorrh. 1971: Suppl. 43: 247-253. 42. TAVENNER, R. W. H.: Epsilon-aminocaproic acid in the treatment of haemophilia and Christmas disease with special reference to the extraction of teeth. Br. Dent. J. 1968: 124: 1-4.
43. WALSH, P. N., RxZZA, (2. R., M/tTTHEWS, J, M., EIPE, J., KERNOFF, P. B. A., COLES, M. D., BLOOM, A. L., KAUFMAN, B. M., BECK, P., HANAN, C. M. & BIOGS, R.: Address: G. RamstrSm Department of Oral and Jaw Diseases Karolinska S]ukhuset 104 01 Stockhohn Sweden
17
Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease; A double blind controlled trial. Br. J. Haematol. 1971: 20: 463-475. 44, WEBSTER, W. P., McMILLAN, C. W., L1UCAS, O. N. & ROBERTS, H. R.: Dental management of the bleeder patient. VIlth Congr. Wld. Fed. Haemophilia. Teheran 1971. ExcerTta Med. 1973: 252: 227-237. 45. WEBSTER, W. P., ROBERTS, H. R. • PENICK, G. D.: Dental care of patients with hereditary disorders of blood coagulation. Mod. Treat. 1968: 5: 93-110. 46. WEBSTER,W, P. tfr ROBERTS, H. R,: Dental treatment of patients with hemorrhagic disorders. The hemophiliac and his world. Bibl. Haematol. (Basel) 1970: 34: 139-140.
Int. J. Oral Surg. 1975: 4:1-17 (Key words: bleeding; hemophilia; hemorrhage; tooth extraction)
Tooth extractions in hemophiliacs GORAN RAMSTROM A N D M A R G A R E T A BLOMB.KCK
Department of Oral and Jaw Diseases and Department of Blood Coagulation, Karolinska S]ukhuset, Stockholm, Sweden
Patients with tendency to bleed can raise considerable problems in oral surgery. A total of 264 teeth and root stumps were extracted in 67 patients with hemophilia A, hemophilia B and yon Willebrand's disease in 118 treatment sessions. An additional four patients with rare coagulation defects were treated. The patient material is divided into three groups in respect to therapy. Patients in Group 1 were given substitution therapy only in connection with the extractions. In Group 2 this form of treatment was supported by fibrinolytic inhibitors and antibiotics, and in Group 3 local hemostatic treatment of the alveolus and acrylic splints were added. It is shown how the substitution therapy and the number of hospitalization days can be markedly reduced, and the postoperative bleedings lessened by changing from treatment according to Group 1 to Group 2, respectively Group 3. It is pointed out that the coagulum formed in the alveolus must be protected from traumatic influence and against the unfavorable influence of saliva by using acrylic splints. Finally, the importance of decreasing local proteolysis through fibrinolytic inhibitors and of reducing postoperative infections by the use of antibiotics has been emphasized. ABSTRACT
- -
(Received for publication 20 March, accepted 15 September 1974)
I n patients with hereditary hemophilia, such as hemophilia A (Factor VIII deficiency), hemophilia B (Factor I X deficiency) or other coagulation disorders, the bleeding risk in tooth extraction is great and the bleeding can prove fatal a~. This applies particularly to the severe ( < 1 % of the factor content; normal range for Factor VIII 65135 % and for Factor IX 60-160 %) and moderate forms (1-5 % of the factor content) of the diseases in question a~. This is also the case in yon Willebrand's diseaseS7 (Table 1). As far as bleeding risks in major surgical intervention are concerned, the
moderate forms can be grouped with the severe forms mentioned above. In the patient material presented by R,MOReNa2 there were also many cases of the mild forms ( > 5 % of the factor content), and experience showed that in these patients, too, considerably increased bleeding was fiwolved in tooth extraction, as well. These mild coagulation disorders are often not diagnosed until a postoperative bleeding occurs, such as following a tooth extraction. Thus, it can be the dentist who discovers the coagulation disorder in the patient suffering from the mild coagulation defectk
2
RAMSTRCJM AND BLOMBN.CK
Table 1. Tooth extractions in patients with hemophilia A and B and yon Willebrand's disease
Author
Year
Bleeding disorder
Ramgren 82
1962
Hemophilia A severe moderate mild Hemophilia B severe moderate mild
Buchanan 8 LeavelP ~ Silwer a7
1956
v. Willebrand's disease
1973
No. of patients
No. of patients reporting bleeding after tooth extraction
71 28 34
12 17 23
19 10 14
10 5 8
95 men 104 women 261"
27 38 134
* 213 patients of the 261 had not received prophylactic treatment (plasma or factor-concentrates). Of these, 131 reported bleedings.
In m a n y hemophiliacs the fear of visits to the d e n t i s t and the resultant bleeding leads to l o n g periods o f dental neglect and i n a d e q u a t e dental care. WEBSTER, ROBERTS & PENICK4~ p o i n t out that "The decayed, missing, filled ( D M F ) rate is considered to be high f o r this young population (average age 20 years). T h e high number o f carious surfaces (D rate), as compared with the n u m b e r o f filled surfaces, indicates that these p a t i e n t s had received little dental care". T h e investigation thus shows that h e m o p h i l i a c subjects p r o b a b l y have a higher caries f r e q u e n c y than other patients who are n o r m M as regards coagulation. This in all l i k e l i h o o d depends on the fact that the former f e a r the often prolonged oozing bleedings which can ensue, even after normal toothbrushing. Therefore, they are frequently less meticulous in their oral hygiene, whereby t h e risk for advanced caries increases c o n s i d e r a b l y with resulting infectious processes and periodontal diseases ~5. Periodontal disease thus advances m o r e rapidly,
which can also entail an increased risk f o r severe acute complications. H e m o p h i l i a c patients therefore form a group where prophylaxis and motivation for a scrupulous oral hygiene are infinitely i m p o r t a n t in t h e reduction of caries and periodontal disease ~. The probable higher caries frequency in hemophiliac patients m a y also be closely related to the fact that the dentist too is faced with increased difficulty when treating these patients '1~. T h e risk of causing lacerations and injury to the mucous m e m brane of the mouth means that a m o r e extensive caries therapy cannot always b e undertaken. It is of vital i m p o r t a n c e t h a t the dental care of hemophiliac patients should b e in the hands of dentists thoroughly familiar with their specific problems. This cannot be over-emphasized 45. One group of hemophiliac patients p a r tictdarly susceptible to gingival bleeding, is that suffering from yon Willebrand's disease. These patients, in addition to their F a c t o r V I I I deficiency, have a p l a s m a factor defect
TOOTH EXTRACTIONS IN HEMOPHILIACS resulting in decreased vascular hemostasis and prolonged bleeding time. This leads to (in addition to hemophilia-like bleedings) an increased tendency towards bleeding from the mucous membranes, resulting in gastrointestinal bleeding, increased and profuse menstrual bleeding and prolonged and irritating gingival bleeding. Patients with severe forms of yon Willebrand's disease are not as common as those with hemophilia A and B, although the number of patients suffering from the mild form is very great. The frequency of bleedings after tooth extraction in this disease is approximately 50 %, according to SILWER'S~7investigations of 1973. As far as the frequency figures for bleedings after tooth extraction are concerned, as given in Table 1 for severe and moderate cases of hemophilia A and B, it should be mentioned that these patients are often aware that they have a coagulation defect before they visit the dentist. Thus, they often are treated prophylactically prior to the tooth extraction, and therefore bleeding complications are fewer than among the mild cases. In the mild group, as previously mentioned, bleeding in connection with tooth extraction is often the first symptom. Thus, as a rule the figures presented are for untreated patients. The figures mentioned by SILWER'~37 above for bleeding complications in yon Willebrand patients shbuld therefore always be seen against this background. SILW,ma7 also reports prophylactic treatment with plasma and factor concentrate upon extractions in 34 of 68 patients. Despite this treatment, eight of these patients afterwards suffered from diffuse bleedtrigs. The introduction of plasma and plasma factor concentrate in the treatment of patients with coagulation disorders has meant much when it comes to reducing the risks of postoperative bleeding. Fresh blood transfusions are usually insufficient to achieve a local hemostasis on tooth extraction 17. It
is naturally better to treat with (fresh) plasma, whereby a greater factor volume can be added with less risk of hypervolemia and congestive heart failurel,10. Often, however, neither is sufficient and one has to resort to treatment with factor concentrate, thanks to which it is now possible to undertake more extensive surgical operations on hemophiliacs, as welllL so. In addition, it must be remembered that the risk of allergic reaction is always present in blood and plasma transfusions. Patients with severe hemophilia A and B can also develop antibody activity (circulating anticoagulants) when treated with blood, plasma or factor concentrate. Furthermore, in all transfusion treatments there remains the risk of transmitting hepatic infection 1~. Different methods have been presented for infusing the lacking factor into patients with coagulation disorders. The most common method, intermittent substitution treatment, implies that the patient receives repeated infusions of plasma or factor concentrate over several days. Here, however, the plasma factor level will vary and if the value is too low, the risk of postoperative bleeding stilt remains. This form of substitution treatment in tooth extraction has been presented by BLOMBXCK& NILSSONs, BJSRLIN & NILSSON-%Zand others. In 1970, M c MILLAN, WEBSTER, ROBERTS ~; BLYTHE23 presented a method for continuous intravenous substitution treatment using a special factor concentrate; this meant that the plasma factor level could be kept constant at the required level. This method is complicated, particularly for the patient, and can hardlsr be considered suitable for routine use. Good results with the fibrinolytic inhibitor E A C A (Epsikapron| in the fibrinolytic bleeding condition have previously been reported 2s. RE~t), LUCAS, FRANSISCO,GEISLER & ERSLEVs3 reported that E A C A had a good bleeding inhibiting effect in tooth
RAMSTROM AND BLOMBXCK extraction. Several other authors, too, have emphasized the importance of E A C A in tooth extraction, with or without substitution therapy.%~,za,4e,4,% WEBSTER, McMmLAN, LUCAS ,& ROBERTS44 showed in 1971 that a high single infusion of Factor VIII - or Factor IX - concentrate complemented with a fibrinolytic inhibitor (EACA) gave good results in tooth extraction. Treatment in accordance with this method has also been used by BJ~RL1N .& NILSSON5. I n other forms of spontaneous bleeding in patients suffering from severe hemophilia, no definite effect of E A C A could be demonstratedlS, zs, '~~ I n April 1969, AB Kabi presented Cyklokapron | (tranexamic acid, AMCA) which has approximately a ten times more powerful anfifibrinolytic activity than Epsikapron. The side effects are also reported to be less for Cyklokapron than for Epsikapron. Local hemostatic treatment of the extraction alveolus, combined with suture and the use of acrylic splints as protection for the coagulum in the alveolus, with or without substitution therapy, have been used as a local means of assistance over a period of years1%14,~4, 41. I n several of these studies fibrinolytic inhibitors also have been used. PIZZONI, CORTELLARO ,• MANNUCC131 have made a comparative study with and without local treatment of the alveolus using both singIe dose and intermittent substitution therapy. Other authors have not availed themselves of local means of assistanceS,ls,'14. The costs for tooth extraction in hemophiliac patients are high, not only regarding the substitution treatment, but also for the medical service. The study here presented is intended to illustrate various ways of decreasing the risks and complications, thus reducing not only the infusion quantity but also the number of days lost through tooth extraction in patients suffering from different forms of coagulation disorders.
Material and methods The clinical material comprised 67 patients treated at the Department of Oral and Jaw Diseases at the Karolinska Sjukhuset during 1965-1973. Sixty-four of these patients were already suffering from known coagulation defects at the time of the first extraction. The material also included three patients whose coagulopathy was diagnosed under the treatment in question, due to postextraction bleedings of long duration. The distribution of the patient material as to the different coagulation diseases, and sex and age, is given in Table 2. In addition to the above mentioned patients, there were four with rare coagulation defects. These four are commented upon separately. A total of 264 teeth and root stumps were extracted, including enucleating a radicular cyst and performing a preprosthetic operation. In 16 of the operations it was necessary to prepare a mucoperiosteal flap and thesehave therefore been captioned as operation (op). The extractions and operations have been performed in 118 treatment sessions. One treatment session is defined as the period of time from the start of treatment, usually the day prior to extraction, or in some cases the extraction day, until no bleeding has occurred for 3-5 days. Generally, this means for Group 1 and 2 the day the patient is discharged from hospital. In the treatment session where two or more teeth were extracted, this has often been perTable 2. Patient distribution in coagulation disorders, sex and age Disease Hemophilia A severe moderate mild Hemophilia B severe (1.4 %) mild v. Willebrand's disease severe mild Total
No. of patients
M
F
Age range
15 9 18
15 9 14
0 0 4
15-51 20-62 9-56
6 4
6 3
0 1
28-48 8-57
2 13
0 2
2 11
29-31 4-81
67
49
18
4-81
T O O T H E X T R A C T I O N S IN H E M O P H I L I A C S t a b l e 3. Patient distribution in the different groups and treated in more than one group
indicating the
No. of patients
Total
number
1
2
3
No. of patients
3 7 9
11 2 8
6 2 7
15 9 18
2 1 4
2 3
3 1
4 1
6 4
1 1
7
2 3
7
2 13
2
1
31
30
27
67
11
3
formed on two or more extraction occasions. One treatment session can thus include one or more extraction occasions (see Figs. 1-3). In all cases except one, where intubation anesthesia was used, the extractions and/or operations were carried out under local anesthesia (Xylocain| 2 %). In n o case did a demonstrable h e m a t o m a appear after the injections. T h e grouping given below can be traced to changes in the methods of treatment. In Group 1, only substitution therapy was used. T h e patients were treated in this m a n n e r during 19651969. Group 2 consists of patients treated with infusion therapy, supported by fibrinolytic inhibitors and antibiotics. This took place during 1969-1971. In G r o u p 3, the G r o u p 2 treatment was supported by local hemostatie means in the extraction alveolus and an acrylic splint attached to the surrounding teeth iu order to protect the coagulum in the alveolus. F o r the majority of patients in Group 1, and all the patients in Groups 2 and 3, a treatment schedule was prepared before the patient was admitted to hospital for extraction. This schedu[e took into consideration t h e degree of severity of the illness and the experience gained from previous treatment. A more detailed account of the treatment principles for the different groups is given below. The distribution of the patients with different coagulation disorders between the three groups is given in Table 3.
of patients
No. of patients in combinations
Groups
Hemophilia A severe moderate mild Hemophilia B severe (1.4 %) mild v. Willebrand's disease severe mild
5
1+2
1+3
2+3
1 1
2
1+2+3
2 1
1
1 5
2
G R O U P 1. S U B S T I T U T I O N T H E R A P Y The patient was admitted to hospital the day before the tooth extraction. Patients suffering from hemophilia A and B received substitution therapy with plasma or factor concentrate immediately before the extraction was performed. The infused quantity for patients with hemophilia A was calculated so that the patient's factor level would rise to 30-50 % of the normal value. The next 2-3 days following the extraction the level was permitted tc~ fall to 25-30 %, and kept at about half this value for 6-10 days. For patients with hemophilia B there was n o Swedish factor concentrate available during the first years, which is why only substitution treatment with plasma could be offered. In consideration of the risk of hypervolemia, the level in these patients on the day of extraction could not b e raised to more t h a n 10-20. The patient was discharged from hospital when he had b e e n free f r o m bleeding, without substitution treatment, for 3-5 days. In patients suffering f r o m yon Willebrand's disease, the substitution treatment was begun the day before the extraction, as these patients show also a slower secondary factor rise, in addition to the primary rise. On several occasions postoperative bleedings of long duration occurred in this group, which necessitated renewed substitution treatment. In some of these cases the "old" bleeding coagulure was removed u n d e r local anesthesia. The
RAMSTR~3M A N D B L O M B * C K alveolus was plugged with Spongostan| and the t a m p o n r e t a i n e d in position by suturing. On the few occasions w h e n severe postoperative infections occurred, penicillin was administered. G R O U P 2. S U B S T I T U T I O N T H E R A P Y SUPPORTED BY FIBRINOLYTIC INHIBITOR AND ANTIBIOTICS All t h e patients in this group were routinely ti'eated with Cyklokapron and penicillin. No p a t i e n t in this group was f o u n d to be oversensitive to penicillin. The treatment with Cykl o k a p r o n a n d penicillin was begun the day bef o r e the extraction, as a rule on the same day as the patient was admitted to hospital. The quantity of plasma and/or factor concentrate was calculated a n d administered during the extraction day, in accordance with what has b e e n said above for Group 1. T h e factor content in the following phase was, however, kept at a lower level a n d the treatment concluded earlier. I n m a n y patients, though, the factor level was raised o n the extraction day only to 20-30 % (in G r o u p 1 30-30 %). This applies m a i n l y to patients treated during the latter haIf of 1970, and 1971, as the experience gained f r o m the c o m b i n e d method of substitution therapy, fibrinolytic inhibitors and antibiotics was considered to justify also an initial lowering of the level. G R O U P 3. S U B S T I T U T I O N T H E R A P Y SUPPORTED BY FIBRINOLYTIC ~ INHIBITOR, ANTIBIOTICS, LOCAL TREATMENT OF ALVEOLUS AND ACRYLIC SPLINT Fibrinolytic i n h i b i t o r and antibiotics were administered as in G r o u p 2. Six patients on 13 extraction occasions were n o t given penicillin, however. One o f those patients reported an oversensitivity to penicillin. In the remaining cases, the risk of infectious complications in extraction was assessed as minimal so the administration of penicillin was n o t considered indicated. Cyklokapron was given perorally, b u t in two of t h e cases intravenously. The quantity of factor concentrate given o n the extraction occasion was calculated as increasing t h e patient's f a c t o r level to 5-10 % of the norm a l value. O n the day a f t e r the extraction either the s a m e quantity was given, or half or none at all, depending u p o n previous experience of the
patient's - or corresponding patient's - respective response to treatment. Immediately prior to the extraction a n alginote impression was taken of the jaw where the tooth to b e extracted was situated. On the plaster cast then made, the or those extraction teeth in question were erased, a n d an acrylic splint of the omnivac type was made. The splint was shaped so that it also covered 3-4 m m of the alveolar process. The tooth was then extracted with as little t r a u m a as possible and the alveolus filled with T h r o m b a s e 500| and T h r o m b a s e dentaire| A piece of Surgicel| was then placed over the alveolus as a shield. The completed acrylic splint was attached to the surrounding teeth with phosphate cement. T h e acrylic splint remained in place for 8-10 days. It should b e pointed out that this acrylic splint must be so shaped that it does not cause decubitus in the surrounding tissues. The first four patients in 1972 were treated with an acrylic splint directly polymerized on t h e teeth 41. This was shaped manually in Paladur| before the tooth extraction. After extraction, Palavit| was applied to improve the fit against the alveolus. However, these splints were very clumsy, so future splints were made according to the omnivac method. P R E P A R A T I O N S A N D H E M O S T A T I C AIDS Blood
Blood transfusions were used on only two occasions, w h e n it was necessary to compensate for blood loss. Plasma Fresh frozen plasma -
Plasma was prepared as rapidly as possible from fresh drawn blood and thereafter frozen at -20 ~, at the latest within 3--4 h o u r s after drawing. (Due to storage problems the adequate t e m p e r a t u r e for maintaining the activity, --40 ~ t o - 7 0 ~, was not used.) It was stored for 2-3 months. Consideration was paid to the blood group of the patient. Factor concentrate Factor VIII concentrate
- A H F concentrate from AB K a b i containing 2-3 units of F a c t o r V I I I a c t i v i t y p e r m l . T h e c o n c e n t r a t e was, as a rule, given with respect to A B e compatibility.
c o n c e n t r a t e - PPSB from Centre National de Transfusion Sanguine, Paris, containing 25 units of F a c t o r I X p e r ml. Factor IX
T O O T H E X T R A C T I O N S IN H E M O P H I L I A C S Preconativ| AB Kabi, containing 25 units of Factor IX per ml.
Fibrinolytic inhibitors Cyklokapron| AB Kabi, aminomethylcyclohexane-carboxylic acid (in Sweden called AMCA). Tablets of 0.5 g have been used in a dosage of 2 tablets 3 times daily. When given intravenously the dosage has been 10 ml at 0.1 g/ml 3 times daily. Analgesics V-penicillin (Calciopen-K| Leo). Tablets of 0.4 g were used. 1.6 g was given daily. Analgesics The only preparation the patients were allowed to use was Alvedon| (Draco). This preparation contains 0.5 g paracetamol per tablet. On some occasions, preparations containing acetyl salicylic acid and some other less suitable preparations have been given inadvertently. Local hemostatics 1. Surgicel| oxidized cellulose preparation from Johnson & Johnson, U.S.A. 2. Spongostan| AB Ferrosan. 3. Thrombase 500| freeze-dried powder containing 500 units of thrombin per bottle, Laboratories de I'ISH, Paris. 4. Thrombase dentaire| bottle containing 2 small sponges, containing total of 100 units of thrombin, Laboratories de I'ISH, Paris. Acrylic splints Paladur| Palavit| and splints prepared according to the omnivac method. C A L C U L A T I O N OF A P P R O P R I A T E AND ADMINISTERED INFUSION QUANTITY During every treatment session the infusion quantity administered and any occurrence of postoperative bleeding have been recorded daily (Figs. 1-3). The assessment of bleedings in all cases has been made by the author (G.R.), with the exception of two daring 1965. For calculation of the requisite factor level, for the extraction occasion, the quantity of factor concentrate or plasma has been counted in units (U). One U has here been defined as the quantity of the coagulation factor present in I ml of fresh plasma. Thus, a patient with severe hemophilia A having a plasma volume of 2,500 ml needs the administration of 500 U
of Factor VIII in order to raise the F a c t o r VIII concentration to 20 (i.e. 0.2 U of Factor VIII per ml plasma). The plasma v o l u m e of the patient has been calculated according to the formula by INIO.EY,BROOKS & Ke~UO~R~0, corrected for hematocrit: (668 + (30 + wt in kg) • (100 -- hematocrit) 1 0 0 - 47 (normal hematocrit) This formula has proved to be satisfactory in the treatment of children and adults ( M . BLOMB~CK,personal communication). Evaluation of the patient's expected plasma factor level on transfusion of a certain quantity of plasma is relatively uncertain as pointed out by BmQs & MACFARLANE1. In tooth extraction in patients with severe hemophilia A, these authors administered plasma to six of the patients. The measured mean value of the factor increase was only 71% of that expected (the highest value being 87 % and the lowest 62 %). The difficulties in obtaining absolutely fresh plasma are great, and we therefore used freshfrozen plasma. The content of the factors contained in the plasma, especially Factor VIII, decreases rapidlyO both at preparation and at storage of plasma at temperatures above --30 ~ to --40 ~. The content of Factor VIII can thus have decreased to 30-70 % of the original value as the plasma was stored under unsuitable conditions. Uncertainty in evaluation has therefore been judged to be great. In the cases where evaluation of the expected factor increase at plasma transfusion was undertaken, the plasma content of Factor VIII was taken to be 0.5 U per ml plasma. The in vitro activity and stability for Factor IX in fresh-frozen plasma is higher than for Factor VIII. The activity for Factor IX has here been evaluated at 0.75 U per ml plasma. The in vivo yield from the quantity of Factor IX administered is, however, considerably lower than in the administration of Factor V I I I and has therefore been evaluated at about one-third zT. The quantity which the patient received (300400 ml pre- and 300-400 ml immediately postoperatively) was based on our previous experience in tooth extraction. Particularly in those patients with yon Willebrand's disease, uncertainty in the evaluation of the factor rise following the administration of plasma is considerable. In these patients there is, in addition to the immediate Factor VIII rise, a secondary rise. Also, the vascular
8
R A M S T R O M A N D BLOMB.~CK
Table 4. D i f f e r e n c e in substitution therapy and hospitalization days in different groups
Disease
Hemophilia A severe < 1% VIII
Hemophilia A moderate 1--4 % V I I I
Hemophilia A mild > 5 % VIII
v. Willebrand's disease
No. of No. of ex. G r o u p patients tracted teeth
1
3
6
2
11
26
3
6
12
1
7
37
2
2
18
3
2
5
1
9
31
2
8
22
3
8
20
1
7
25
2
5
12
3
7
18
Hospitalization days
AHF ml
Total: Per tooth: Total: Per tooth: Total: Per tooth:
45 7.5 95 3.7 32 2.6
6,300 1,050 15,600 600 2,100 175
7,600 1,260 4,800 185 0 0
19,550 3,260 41,400 1,592 5,250 438
Total: P e r tooth: Total: Per tooth: Total: Per tooth:
11 3 29 1.6 3 0.6
3,200 86 2,800 156 200 40
56,100 1,516 2,400 133 0 0
36,050 974 8,200 456 500 100
Total: Per tooth: Total: Per tooth: Total: Per tooth:
92 3 17 0.8 3 -
1,700 55 700 32 0 0
41,200 1,330 600 27 0 0
24,850 802 2,050 93 0 0
Total: Per tooth: Total: Per tooth: Total: Per tooth:
70 2.8 24 2 0 0
1,500 60 900 75 0 0
29,400 1,176 6,250 520 0 0
18,450 738 5,375 475 0 0
Plasma No. of ml units*
Fact. IX conc.
Hemophilia B <~ 1.4 % I X
Hemophilia B > 2 % IX
* I n v i t r o value
1
2
3
2
3
7
3
4
6
1
3
8
2
1
2
3
1
3
Total: P e r tooth: Total: Per tooth: Total: Per tooth:
27 9 34 4.9 21 3.5
200 67 160 23 120 20
10,800 3,600 9,800 1,400 0 0
13,100 4,366 11,350 1,621 3,000 500
Total: Per tooth: Total: Per tooth: Total: Per tooth:
27 3.4 8 4 0 0
0 0 0 0 0 0
15,450 1,930 1,000 500 0 0
11,690 1,460 750 375 0 0
TOOTH EXTRACTIONS IN HEMOPHILIACS effect of the bleeding time factor cannot be assessed as there is no acceptable determination method for this particular factor. The determination of the bleeding time according to Duke was performed in some of the cases to confirm that the patient had a satisfactory vascular hemostatis~-~. In the treatment of patients with yon Willebrand's disease, transfusion treatment was, as mentioned, often begun the day prior to the tooth extraction in order to exploit the secondary Factor VIII riseL Before and precisely half-an-hour after completed treatment, samples were taken for analysis of the patient's plasma factor level. It has previously been shown that this particular time was best for the measurement of an optimal level (hemophilia A and B)8. The half-life for Factor VIII has been evaluated to be about 9-18 hours, and for Factor IX 18-40 hours~7.
different groups is shown in Table 4. A s has previously been pointed out, a changeover from plasma and/or factor concentrate therapy in Group 1 and 2 to only factor concentrate in Group 3 took place. I n order to reach an approximate assessment of the quantity of substitution therapy per tooth in the different groups, an evaluation of the in vitro number of units (U) was made. As shown in Table 4, the quantity of preparations for the severe hemophilia A cases decreased from 3260 U/tooth in Group I to 1660 U/tooth in Group 2 and to 440 U / t o o t h in Group 3. The number of days in hospital was correspondingly reduced. A good comparison between the treatment results is reflected also in the patient examples given in Figs. 1-3. A summary of the number of bleeding complications in the different groups is given in Table 5. In Group 1, postoperative bleedings occurred in 59 % of the treatment ses-
Results A summary of the substitution quantity and of the number of days in hospital for the
,.~ 20 x z
16
i-~
IO
B.B, As EXTRACTION JUNE" JULY 196g IGROUP 21
~O0O a
J FACTOR CONCENTRATE
900 = t PtAS.A
6OO
~d
5
27
30 '~ zs
9 NEASURED FACTOR-LEVEL
&DO ~
28
29
30
,, ill Jilt11 I
2
:1
S
&
6
?
9
+ BLEEDING Z00
DATE
M.L. A M EXTRACTION NOV. 1969 (GROUP 2) IEXe_LI LExLL~.
EXTRACTION JAoN.1970 (GROUP 2)
IEXI~
20
ixUL~ [EXZ_!I
9
>
F EDD .~
5
~
"/
I I 8
9
10
II
12
tll 13
I&
15
IIS
I?
10
/
,, /
I&
IS
t6
17
16
Ig DATE
Fig. 1. A8 means hemophilia A severe form, A~o means hemophilia A moderate form, ML see also Table 6. For explanation of preparations and units infused, see p. 7.
RAMSTR~3M A N D BLOMB~_CK
10
U.H. AMo EXTRACTION JAN. 1969 (GROUP 1 ) .., < X
25
~= zo
$ /,00
z
.J tu
r,
m
,,=
I I :i
s 10
30
II
12
t3
+
I/.
§
tS
lS
17
18
~
10
§
20
§
11
22
2~1
2&
DATE
P.O,S. B s OPERATION MARCH-APRILlgBg (GROUP 11
[Ex~
. , 2S ,4 Z *~o 20 z
o~
ig
s00
is
_z
600
d
,,', 10
x S
13
1/,
lS
16
17
16
19
4
20
"2.1 §
22 +
23 9
24 +
2S
26
2'7
§
28
29
30
31
1
2
DATE
§
Fig. 2. A~[O m e a n s hemophilia A moderate form. Bs means hemophilia B severe form. F o r explanation of preparation and units infused, see p. 7.
Table 5. Bleeding complications in different groups and diseases
Disease
Memophilia A severe 9m o d e r a t e mild Memophilia B severe mild v. Willebrand's disease Total
Group No. of treatm, session
1 No. of bleeding compl.
Group 2 No. of No. of treatm, bleeding session compl,
Group. No. of treatm, session
3 No. of bleeding compl.
3 9 11
3 7 8
13 3 9
5 0 4
6 2 11
2 0 1
2 2 12
2 1 2
3 2 6
0 0 1
5 3 13
1 0 0
39
23
36
10
40
4
TOOTH EXTRACTIONS IN HEMOPHILIACS 2O
o~ t5
B.S. A s EXTRACTION 2o. R,S.A s EXTRACTION 20, G.T.H,As EXTRACTION MARCH 1972 (GROUP31 MARCH19721GROUP3) APRIL 1972 {GROUP 3) [ExlJ~ 1~
.,a t O -"
11
5
f
~O0
IO
/,0o
5
15
K.G.J
16 * 17
(GROUP
]
2O0
19
B sEXTRACTION
NOV. 1969
f
~00
20o
>
.oo
I0
llO0
,
20
21
1
2
]
/,
5
6
7
' $
f
,Do
9
10
I1 DATE
zO
1/,00
3) 1200
2o =o z
Is
, tO00
BOO
20 15
600 &00
> ~u
5
200
S"
K.G.J, Ps EXTRACTION 20 - S.L. Bs EXTRACTION JAN.t972 (GROUP 3) OCT. 1973 (GROUP 3 ) [Ex L~ ,s ,?,
~
6D0
10'
L00 ZC0
~oo
5'
201)
o~ 2/*
'25
26
Fig. 3. AS means hemophilia A severe form. BS means hemophilia B severe form. For explanation of preparation and units infused, see p. 7.
sions. In Group 2, the Needing frequency decreased to 28 %, and in Group 3 it was reduced to 10 %. It should also be pointed out that the bleedings in Group 1 were far more frequent and prolonged than those o c c u r r i n g ' i n Groups 2 and 3. Nine of the bleedings in Group 1 were described as severe and prolonged, but in Groups 2 and 3 there was no such bleeding. Patients with moderate forms of hemophilia A were found to be relatively difficult to treat according to the method used for G r o u p 1. M a n y of the postoperative bleedings registered were particularly prolonged and complicated. This patient category responded very well to Cyklokapron and antibiotic therapy and no bleedings were registered in G r o u p 2. Several patients with miId forms and even m o d e r a t e forms of hemophilia and mild forms of votz Willebrand's disease could be treated as outpatients when changed over to treatment according to G r o u p 2,
and later to Group 3. This has lightened the hospital's burden considerably. Extractions have also been performed on patients with rare coagulation defects. T w o patients with a mild Factor X deficiency and two patients with a m i l d F a c t o r X I deficiency have thus been treated. T h e patients were first given large quantities of plasma. Later, following the administration of fibrinolytic inhibitors and antibiotics, the plasma treatment could be discontinued. One p a tient developed hepatitits after plasma treatment in 1967.
Discussion The main causes of bleeding in tooth extraction in patients with coagulation defects are alleged to be (1) too low a level of the lacking coagulation factor, (2) local fibrinolysis and (3) traumatic injury to the coagulum formed.
12
RAMSTROM AND BLOMB,~CK
In Group 1, where only substitution therapy was applied, the factor level in several cases was in all certainty too low to give a good coagulum. T h e bleedings often started within the first 24 hours following the extraction. In those cases in which the factor level was acceptable from the hemostatic point of view, several of the postoperative bIeedings were probably caused by local fibrinolysis4dl,etk I n these patients the bleedings often began 3-5 days after the extractions. W h e n substitution therapy was instituted, as in Group 1, with a calculated initial factor level of 30-50 % and subsequently 15-30 % during 2-3 days after the extraction, this level clearly proved too low if at the same time there seemed to be local fibrinolysis and severe infection in the alveolus. It must be remembered that, generally, the indication for tooth extraction in patients with_ various coagulation defects is most usually teeth gravely affected by caries and osteitis. (In one of the cases reported in this study, there were orthodontic indications for extraction.) Whether or not the primary infection increased, the fibrinolytic activity cannot be established with any degree of certainty, as no such laboratory examinations took place. It is quite possible that when the coagulum disintegrates owing to local fibrinolysis, the all too low factor level does not suffice for the formation of a n e w coagulum, and diffuse bleeding ensues. When a new transfusion was given, the factor level rose, a new coagulum was formed a n d the bleeding ceased. In some of the cases in Group 1 this occurred 3-5 times before a healing of the alveolus was attained. It is known to be very important that the patient does not begin to bleed, as this entails an increased consumption, and hence a more rapid drain of the faetor administered. In order to stop the postoperative bleedings, 14 of the patients in Group 1 were treated by plugging with absorbable go-
latinous sponge (Spongostan), and suturing. In eight of these cases, plugging took place without antibiotic protection. T h e result in all of these cases was a violent swelling at the operation site and a rapid rejection of the plug. In all probability, this was caused by. an infection encapsulated in the alveolus by the hemostatic plug, and the consequent action of the foreign body resulted in the rejection of the pIug. In those cases in which antibiotics were administered, however, this tendency towards rejection was not seen. Thus, clinically, we have observed a good local effect of the antibiotic therapy in six of the cases in Group 1. These locally observed clinical advantages in the antibiotic treatment of patients with different bleeding diseases were the reason for the routine use of penicillin with the introduction of fibrinolytic inhibitors in April 1969. There is reason to believe that the antibiotic therapy initially protected against infection, thus probably decreasing the local fibrinolyric action. However, there are still no examinations confirming that this Iocal fibrinolysis would be decreased by the use of antibiotics. That this local fibrinolysis played a large part in subsequent bleedings is shown by the favorable results following the introdudtion of fibrinolytic inhibitors and antibiotics in Group 2. Thanks to these preparations the quantities of the infusions and the number of days in hospital could be considerably reduced. The postoperative bleedings, very worrisome and irritating to the patient, decreased manifestly upon the change to treatment according to Group 2. This also implies a considerable saving of labor for the staff of the department where the patient is hospitalized. These good results achieved in changing from treatment according to the method in Group 1 to the method in Group 2 included decreased risk of complications and reduced substitution quantities and number of days
TOOTH EXTRACTIONS IN HEMOPHILIACS in hospital. Several authors, as has previously been pointed out, have reported good results with local treatment of the alveolus combined with acrylic splints. It has also been possible to undertake tooth extraction according to these methods in patients with circulating anticoagulants41. In an attempt to further minimize the complication risks in tooth extraction, it was decided to try treating the alveolus locally and using acrylic splints to protect the coagulum in the alveolus. As seen from Table 4, there was a decided improvement in the treatment results when the previous general methods of treatment were complemented with local methods. The reasons for these improved results when changing from the treatment method of Group 2 to that of Group 3 are probably several. The coagulum formed in the alveolus was well embedded in an absorbable gelatinous sponge (Thrombase dentaire). Thrombine powder (Thrombase 500) gave a quicker and more stable coagulation. The task of the well-attached acrylic splint should at least have been two-fold. SCHULTE & W/SRNER 86 demonstrated a deteriorated coagulum formation on contact between blood and saliva. Acrylic splints have been able to reduce considerably both this unfavorable effect of the saliva flow and also the risk of traumatic injury to the coagulum. A direct evaluation of the different parts of this local hemostatic supporting treatment is, however, difficult. In patients with severe and moderate forms of coagulation disorders, however, local alveolar treatment and the use of an acrylic splint seem to be necessary if the factor level is to be kept low, even when penicillin and Cyklokapron are administered. In patients with the mild forms, the supporting local treatment is not generally necessary because the fibrinolytic inhibiting effect of Cyklokapron, possibly combined with antibiotics, is sufficient. It has been proved by experience that it is
13
possible to extract several teeth on one extraction occasion, provided that a sufficient number of teeth remain for the atfixation of the acrylic splint. Comparing the treatment results for patients treated by different methods on separate extraction occasions, many interesting observations can be made (Table 6 and Figs. 1-3). RA was treated as a Group 1 patient in 1968, then receiving a total of ca. 4,100 U. On extraction 1 year later in Group 2, he received 1,700 U, this time with reduced postoperative bleeding. AJ in 1967 received as a Group 1 patient 3,000 U in the form of plasma. The extraction 3 years later as a Group 2 patient necessitated ca. 1,000 U, and as a Group 3 patient in 1972 only 500 U. Observations of the factor level at the time of extraction show that this can be kept considerably lower than the 40 % suggested by BJORLIN.& NILSSON8 and still give entirely acceptable hemostasis: without postoperative bleeding. In the five extraction sessions of severe hemophilia B patients, the factor level was calculated to lie between 5 and 10 %. Here, only one patient showed an insignificant postoperative bleeding, probably due to a factor level of 0.2 % on the extraction occasion (suspected case of circulating anticoagulants). This all too low factor level in all certainty did not give an adequate coagulum, which may have been the cause of the postoperative bleeding. This bleeding stopped nicely, though, upon the intravenous administration of Cyklokapron only. LUCAS, CAKROL, FINKELMAN ,~; TOCANTINS 2:2 a n d LUCAS, FINKELMAN ,~,~ TOCANTINS2~ used hypnosis in tooth extraction with good results in patients with coagulation defects. Here it is of the utmost importance that the patient is calm and has confidence in the physician and dentist treating him. Therefore, patients who are anxious and nervous concerning the postoperative
RAMSTROM AND BLOMBXCK
14
Table 6. T o o t h extractions performed in the same patient in different groups (1, 2 a n d Patients are g r o u p e d for comparison purposes Patient's initials RH GTH RA RS BS ML
Disorder Hemophilia severe Hemophilia severe Hemophilia severe Hemophilia severe Hemophilia severe
A A A A A
Hemophilia A moderate
RGJ
Hemophilia A moderate
GTo
Hemophilia mild Hemophilia mild Hemophilia mild Hemophilia mild
WL GTe NB
YJ
AJ
KGJ
A A A A
Hemophilia A mild Hemophilia B severe
Hemophilia B severe
AR
y o n Willebrand's disease mild
ACJ
yon Willebrand's disease mild
MB
y o n Willebrand's disease mild
No. of extracted teeth
Hospitalization days
3 6 2 4 1 1 2 1 4 1
27 15 6 15 12 I0 8 5 9 4
12,000
5 11 5 1 4 op
10 15 7 4 3
4,200
1 1 1 1 2 12 1 1 op 2 1 1 1
0 0 2 0 10 13 3 0 0 1 0 0
2 1 1 1 2 2 1
No. of units infused Gr. 1
Gr. 2
Gr. 3
3,750 2,200 1,000 4,150 1,750 2,500 250 3,000 750 4,500 2,250 1,200 500 250 400 1,050 1,250 800 0 0 0
8 6 5 3 3+3 8 6
3,000
1 op 2 1 1 1 2 1 1 1
8 11 2 2 2 2 0 5 2
3,000 3,050
i op 1 op 1 op
3 0 0 0
1 op
3).
1,700 1,000 500 500 3,250 1,000
300
150 350 200 800 400
TOOTH EXTRACTIONS IN HEMOPHILIACS course should be retained in hospital for an extra day or two. It is also of the utmost importance that patients with coagulation defects, at least in severe and moderate cases, are familiar with the physician and dentist treating them. It is well known that a satisfactory platelet function including platelet aggregation, is necessary both for the primary hemostasis and for the activation of the coagulation mechanism. Blocked platelet aggregation is to b e observed after treatment with acetyl salicylic acid, and also after certain other medicaments (phenylbutazon, indomethazin)m. It is thus very important to avoid such medicaments in order to achieve a quick primary hemostasis and stable coagulurn. The Department staff was instructed to administer no painkiller other than Alvedon| (paracetamol). Despite this, by an oversight nine patients received medicaments containing acetyl salicylic acid. The five postoperative bleedings which occurred in these nine patients can have been caused, or at least aggravated, by the decreased platelet aggregation. T w o of the three patients whose coagulopathy was revealed by bleeding after tooth extraction had, on the extraction occasion in question, used preparations containing acetyl salicylic acid. Concerning patients with a severe form of y o n Willebrand's disease, our experience, as shown by the tables, is little. However, it would seem desirable, even though local hemostatics and the acrylic splint are used, to use sufficient substitution therapy to normalize the bleeding time ( ~ 7 rain accord]ng to Duke).
Acknowledgments - The authors wish to express their sincere gratitude to professors
OUNNAR M~TENSSON, CARL-AxELHAMBEROER and Ar~ NO~DBNRAM for valuable help and inspiring discussions and to Mrs. ULLA WALLINDER for valuable assistance.
15
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16
RAMSTRt3M AND BLOMB.KCK
15. GIORDANO, N. D., WATKINS, R. S., RAmVOYVITCH, M. O., GooDsrrr, E.: Dental extractions in hemophilic patients on aminocaproic acid prophylaxis. Oral Surg. 1968: 26: 160-166. 16. GLOGOFF, M., BAUM, S. M., SUSSMAN, R., STEWART, S. & STOOVACK,J. C.: Management of the hemophilic oral surgery patient, I. Oral Surg. 1972: 30: 252-262. 17. I--IAXmERO,L., RAMOILEN, O. t~ TENGBERG, J.-E.: Nya erfarenheter i samband reed tandextraktioner p~ blSdare. Sven. Tandlaek. Tidskr. 1959: 52: 293-299. 18. H&YTON-u D. S.: Oral surgery on the haemophilic patient. In: WALTER, R. V. (ed.): Trans. Congr. Int. Assoc. Oral Sarg. 1970, p. 496-499. 19. I_~ogaM, G. I. C.: Dental care in haemophilia. T h r o m b . Diath. Haemorrh. 1971: Suppl. 43: 213-218. 20. INKLEY, S. R,, BROOKS, L. & KREUGER,H.: A study of methods :for the prediction of plasma volume. J. Lab. Clin. Med. 1955: 45: 841-850. 21. KANESHIRO, M. M., MIELKE, C. H. Jr., KASI'ER, C. K. & RhPAI~ORT, S. J.: Bleeding time after aspirin in disorders of intrinsic clotting. N e w Engl. J. Med. 1969: 281: 1039-1042. 22. LOCAS, O. N., CARROL, R. T., FINKELMAN, A. & TOCANTrNS, L. M.: Tooth extractions in hemophilia. Control of bleeding without use of blood, plasma or plasma fractions. T h r o m b . Diath. Haemorrh. 1962: 8: 209220. 23. LUCAS, O. N., FINKELMAN,A. &TOCANTINS, L. M.: Management of tooth extractions in hemophiliacs by the combined use of hypnotic suggestion, protective splints and packing of sockets. J. Oral Surg. 1962: 20: 488-500. 24. MCINTYRE, H.: Dental extractions in patients with hemophilia syndrome. Oral Surg. 1965: 19: 163-173. 25. McMrLLAN, C. W , WEBSTER, W. P., RoaERTS, H. R. & BLYTnE, W. B.: Continuous intravenous infusion of factor VIII in classic haemophilia. Br. J. HaematoI. 1970: 18: 659-667. 26. MEOQUmR, R. J.: Fibrinolytic activity in human dental sockets after extractions, J. Oral Surg. 1971: 29: 321-328. 27. NILSSON, I. M.: Bl6dnlngs- och tromboss#tkdomar. AB Kabi, Atmqvist & Wiksell, Stockholm 1971.
28. NILSSON, I. M. & BJORKMAN, S. E.: Clinical experiences with e-aminoeaproic acid (~ACA) as an antifibrinolytic agent. Acta Med. Scand. 1961: 170: 487-509. 29. NILsso~, I. M. & BLOMBXCK, M.: yon Willebrand's disease in Sweden - occurrence, pathogenesis and treatment. Thromb. Diath. Haemorrh. 1963: 9: Suppl. 2: 103-118. 30. NILSSON, I, M., BLOMB.~CK, M. & RAMOREN, O.: Haemophilia in Sweden. VI. Treatment of haemophilia A with the human antihaemophilic factor preparation (Fraction 1-0). Acta Med. Scand. 1962: Suppl. 379: 61-110. 31. PIZZONI, D., CORTELLARO, M. t~ MANNUCCI P.M.: Replacement therapy and local measures for dentat extractions in haemophiliacs: a comparison of various schemes of treatment. VIIth. Congr. Wld. Fed. Haemophilia. Teheran 1971. Excerpta Med. 1973: 252: 242-244. 32. RAMGREN, O.: Haemophilia in Sweden. III. Symptomatology with special reference to differences between haemophilia A and B. Acta M e d . Scand. 1952: 171: 237-242. 33. REID, W. O., LUCAS, O. N., ~,ANSISCO, J., GEISL~R, P. H. & ERSL~V, A. J.: The use of epsilon-aminocaproic acid in the management of dental extractions in the hemophiliac. Ant. J. Med. Sci. 1964: 84: 184188. 34. ROKICKA-MILF.,WSKA, R., KRAJEWSKA-MARTEL, A. & DVSZY-LAunE, B.: Application of epsilon-aminocaproic acid for oral mucosal bleedings in haemophiliacs. Pol. Arch. M e d . W e w n . 1966: 4/10: 445. 35. RUBIN, B., LEVINE, ]3. 8z ROSENTHAL, M. C.: Complete dental care of the hemophiliac. Oral Surg. 1959: 12: 665-675. 36. SCHm-TE, W. & W6RNER, H.: Speicheieinfltisse auf die Blutgerinnung bei hS_morrhagischen Diathesen - thromboelastographische Untersuehungen. Dtsch. Z a h n aerztl. Z. 1968: 23: 835-843. 37. StLWER, J.: yon Willebrand's disease in Sweden. A c t a Paedialr. Scand. 1973: Suppl, 238. 38. SINCLAIR, J. H.: Current concepts in the dental treatment of haemophiliacs. T h r o m b . Diath. Haemorrh. 1971: Suppl. 43: 203-212. 39. SKOELD, E.: On haemophilia in Sweden and its treatment by blood transfusion. Acta M e d . Scand. 1944: 117: Suppl. 150: 165.
TOOTH EXTRACTIONS IN HEMOPHILIACS 40. STRAUSS, H. S., KEVY, S. V. & DIAMOND, L. K.: Ineffectiveness of prophylactic epsiIon aminocaproic acid in severe hemophilia. New Engl. J. Med. 1965: 273: 301304. 41. SZeIRGLAS,H.: L'h6mostase locale dansles extractions dentaires chez l'h6mophile. Thromb. Diath. Haemorrh. 1971: Suppl. 43: 247-253. 42. TAVENNER, R. W. H.: Epsilon-aminocaproic acid in the treatment of haemophilia and Christmas disease with special reference to the extraction of teeth. Br. Dent. J. 1968: 124: 1-4.
43. WALSH, P. N., RxZZA, (2. R., M/tTTHEWS, J, M., EIPE, J., KERNOFF, P. B. A., COLES, M. D., BLOOM, A. L., KAUFMAN, B. M., BECK, P., HANAN, C. M. & BIOGS, R.: Address: G. RamstrSm Department of Oral and Jaw Diseases Karolinska S]ukhuset 104 01 Stockhohn Sweden
17
Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease; A double blind controlled trial. Br. J. Haematol. 1971: 20: 463-475. 44, WEBSTER, W. P., McMILLAN, C. W., L1UCAS, O. N. & ROBERTS, H. R.: Dental management of the bleeder patient. VIlth Congr. Wld. Fed. Haemophilia. Teheran 1971. ExcerTta Med. 1973: 252: 227-237. 45. WEBSTER, W. P., ROBERTS, H. R. • PENICK, G. D.: Dental care of patients with hereditary disorders of blood coagulation. Mod. Treat. 1968: 5: 93-110. 46. WEBSTER,W, P. tfr ROBERTS, H. R,: Dental treatment of patients with hemorrhagic disorders. The hemophiliac and his world. Bibl. Haematol. (Basel) 1970: 34: 139-140.