Etiology and pathogenesis of fibrinolytic alveolitis (“dry socket”)

Int. J. Oral Surg. 1973: 2 : 2 1 1 - 2 6 3 (Key words: alveolitls; dry socket; /ibrinolysis)

Etiology and pathogenesis of fibrinolytic alveolitis ("dry socket") H. BIRN

Department of Oral Surgery, Royal Dental College, Aarhus, Demnark

Thesis

This dissertation, together wkh the previously published articles listed on the following page, has been accepted by Aarhus Dental College as published defense for the degree of Doctor of Odonlology.

This thesis is based on tile following previously published investigations contained in the following articles: I. BriaN, H.: The vascular supply of the periodontal membrane, An investigation of the number and size of perforations in the alveolar wall. J. Periodontol. Res. 1966: 1: 51-68. II. BIr~r~, H.: Fibrinolytic activity in "dry socket". Acta Odontol. Scand. 1970: 28: 37-58. III. BIRN, H.: Bacteria and fibrinolytic activity in "dry socket". Acta Odontol. Scand. 1970: 28: 773-783. IV. BtRN, H.: Fibrinolytic activity of normal alveolar bone. Acta Odontol. Scand. 1971: 29: 141-153. V. BIRN, H.: Fibrinolytic activity of alveolar bone in "dry socket". Acta Odontol. Scand. 1972: 30: 23-32. VI. B1rtN, H.: Kinines and pain in "dry socket". Int. J. Oral Surg. 1972: 1: 34-42. VII. BIRN, H. & MYHRE-JENSEN, O.: Cellular fibrinolytic activity of human alveolar bone. Int. J. Oral Surg. 1972: 1: 121-125. In the following, the above-mentioned articles will be referred to by the stated Roman numerals.

Preface The present work was performed during the years 1963 to I972. In this period I was employed partly in the Department of Anatomy (one year) and partly in the Department of Oral Surgery, the Royal Dental College, Aarhus. The various investigations on which this thesis is based could never have been carried out without valuable help from various persons attached to the above-mentioned departments and to other departments within the Royal Dental College as well as persons attached to the Municipal Hospital and the County Hospital of Aarhus. As I feel it impossible to emphasize one invaluable effort before all others, I have decided to list all persons who have assisted in alphabetical order, expressing my sincere gratitude for their highly appreciated contributions to the fulfillment of this thesis.

O. K. Albrechtsen, Chief Surgeon, M.D., Dr. Med. E. Andersen, Chief Technician B. Birn, D.D.S., my wife M. Glahn, Professor, M.D., D.D.S., Dr. Med. B. Gottliebsen, Secretary P. Junker Jacobsen, Chief Librarian H. Aslaug Jensen, Technician B. Dorph Jensen, D.D.S. T. Karritzg, D.D.S. J. Kirkegaard, Medical Illustrator P. A. Knudsen, Professor, M.D., D.D.S., Dr. Med. O. Myhre-Jensen, Chief Physician, M.D., Dr. Med. I. Steen Petersen, Secretary H. P. Philipsen, Professor, D.D.S., Dr. Odont. J. E. Winther, Associate Professor, D.D.S. In addition I wish to thank the Danish State Medical Research Council which supported one of the investigations with Grant No. L-1465/66. Aarhus, September 1973 Herlu[ Birn

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS

215

Contents Chapter ] INTRODUCTION

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Chapter 2 C L I N I C A L P I C T U R E A N D P A T H O G E N E S I S ......................................... 218 A g e and sex distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 Distribution within the dental arches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 Distribution a c c o r d i n g to single and multiple extractions . . . . . . . . . . . . . . . . . . . . . . . 220 Seasonal variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Onset and d u r a t i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 N o r m a l healing o f e x t r a c t i o n w o u n d s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Healing in fibrinolytic alveolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 Pain: and fibrinolytic alveolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 C o n c l u s i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

Chapter 3 E T I O L O G Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 G e n e r a l factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Local factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 Insufficient blood supply to the alveolus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 Pre-existing infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Local anesthetics w i t h vasoconstrictor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 P o s t o p e r a t i v e bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 T r a u m a to the alveolar bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 I n f e c t i o n of the alveolus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 R e m a i n i n g r o o t or b o n e fragments or foreign bodies in the alveolus .. 229 Excessive irrigation or currettage of the alveolus after extraction ........ 229 H e a v y sucking or spitting postoperatively . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 I n c r e a s e d fibrinolytic or proteolytic activity in the b l o o d clot ........... 229 Conclusion and s t a t e m e n t o f problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

Chapter 4 B L O O D S U P P L Y T O T H E A L V E O L I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

BIRN

216

Chapter 5 FIBRINOLYSIS ................................................................................... General aspects ............................................................................. P o s s i b l e causes of fibrinolysis in f i b r i n o l y t i c alveolitis . . . . . . . . . . . . . . . . . . . . . . . . . .

235 235 236

Chapter 6 FIBRINOLYTIC

ALVEOLITIS

Chapter 7 ETIOLOGY OF FIBRINOLYSIS

AND

FIBRINOLYSIS

IN FIBRINOLYTIC

.............................

238

A L V E O L I T I S ........... 2 4 0

General Iibrinolysis ....................................................................... F i b r i n o l y s i s in saliva . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bacterial f i b r i n o l y s i s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T i s s u e fibrinolysis o f the j a w b o n e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T i s s u e fibrinolysis in f i b r i n o l y t i c alveolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion ...................................................................................

240 240 241 242 245 246

Chapter 8 FIBRINOLYTIC ALVEOLITIS AND KININS ......................................... General aspects ............................................................................. K ! n l n s in f i b r i n o l y t i e alveol!t~,s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion ...................................................................................

248 248 248 250

Chapter 9 CONCLUSIONS CONCERNING ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS ........................................................

251

Chapter JO FINAL

REMARKS

SUMMARY

.............................................................................

254

.........................................................................................

255

REFERENCES

...................................................................................

257

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS

217

CHAPTER 1

Introduction " D r y socket" is the term most frequently used for a rather common and very unpleasant local complication of the extraction or surgical removal of teeth. The clinical appearance of this disease is well known and was first described in 189647: Two or three days after removal of the tooth, disintegration of the normal blood clot occurs. The alveolus is empty, with completely or partially denuded, very sensitive bone surfaces, covered by a grayish-yellow layer of detritus and necrotic tissue. The surrounding gingiva often shows inflammatory reactions. The patient complains of heavy pain of a neuralgic character. F r o m an alveolus of the mandible the pain irradiates towards the ear and the temporal region. F r o m an alveolus of the maxilla the pain irradiates towards the eye and frontal region. Halitosis is pronounced, and the patient complains of a bad taste in the mouth. Swelling of the regional lymph nodes is rather common. General symptoms such as increased temperature are hardly ever seen, but the patients may be psychically affected because of the heavy pain and feel unwell due to lack of sleep and appetite. Like other diseases for which the etiology and pathogenesis have not yet been determined, this disease also has acquired numer-

ous names. They mainly characterize the clinical picture of the disease. The expression "dry socket" is the earliest name which clearly separates the disease from other complications of tooth extraction47. Others are: alveolalgias2, alveolitis sicca dolorosa74, avascular socket, dolor post extractionen 32, epithelialized socket 1~ leeren Alveole~Q, necrotic alveolar socket, painful socket1~ ol. A number of other designations of this disease refer to the pronounced local osteomyelitis, which is a constant finding in the surrounding bone marrow: alveolar osteitisa, 2os, alveolitis, circumscribed osteitic foci, localized osteitisX~ t~~ ostitis post extractionem lx4, localized acute alveolar osteomyelitis5~ postexodontic alveolar osteitisl~ and postextraction osteomyelitic syndrome ~ In this thesis the disease will be called fibrinolytic alveolitis (FA). The reason for this will be explained in detail later on. As previously mentioned, the etiology and pathogenesis of F A are only inadequately known. The purpose of the present work has therefore been, on the basis of a study of the reports on the many suggested etiologies of FA, to find the most probable ones and subject these to a more detailed investigation to try to elucidate the etiology of FA.

218

BIRN

CHAPTER 2

Clinical picture and pathogenesis AGE AND SEX DISTRIBUTION Extensive clinical investigations have shown that the disease develops in 2.0 to 4.4 % of all extractions of permanent teeth 3, 71, 7~, 74, o2102. The average of all statements is 3.0 %. Only Archer ~5 finds an appreciably lower frequency, viz. 0.9 % (Table 1). F A most frequently occurs in the age group os 20 to 40 years 41, 9~, 102. According to these authors, between 25 and 80 % of all cases of F A are found in this age group. Almost no cases of F A are seen before the 18th year or after the 50th 41, 0,, 10~. Thus, only Gustafson & Wallenius6~ have reported cases of F A after extraction of primary teeth (7 cases after t0,000 extractions). Lehner ~s explains the age distribution in F A by the fact that the highest incidence occurs in the period of time when the third molar, which has a high incidence of FA, erupts and is removed. This explanation is, however, hardly valid for the total period from 20 to 40 years, when the incidence of F A is especially high. It is contradicted by his own findings, too. They show that 39% of all cases of F A occur in the age group of 18 to 25 years and 47 % in the age group of 25 to 45 years, whereas most wisdom teeth erupt in the former period. Finally, Lehner ~ does not state the number of extractions performed in the individual age groups, and a frequency of F A within each group can therefore not be calculated. MacGregor 1~ mentions the remarkable fact that F A most frequently occurs in relatively young age groups and

not in the older ones, where postoperative complications otherwise are most frequent. He does not give any explanation os this phenomenon. Some authors state that there is no difference in the sex distribution of F A ~ 0~ Mac Gregor 1~ on the other hand, states that FA occurs more frequently in women than in men (<3:~ = 2 : 3 ) and is the anly author whose results are statistically supported. The author does not give any explanation of this sex distribution, but it may be searched for in the fact that women on the whole are more aware of diseases and therefore more often will seek treatment for disease.

DISTRIBUTION WITHIN T H E D E N T A L ARCHES FA most frequently occurs after extraction of martdibular teeth 3,15, 41, 71, 72, 74, 91, ~5, 102, 142. The statements of the occurrence in the mandible vary from 58 %70. to 92 %01 of all cases of FA, the mean being 73 %. In the mandibIe most cases of F A occur in the molar area. The highest percentage of F A is in the first and third molar areas, where the statements of incidence range from 14 to 30 % of all cases of FA. The only exception is the statement by Krogh ~1, which claims the highest incidence of F A is in the mandibular second molar area (30 %). According to the above-mentioned authors F A is seldom seen in the front region (from 0 to 2 % of all cases of FA). But these statements must be taken with certain reservations as

ETIOLOGY AND PATItOGENESIS OF FIBRINOLYTIC ALVEOLITIS Table 1. The occurrence of fibrinolytic alveolitis (FA) in percent after removal of permanent teeth

Author

Krogh 91 Archer15 Adkisson & Harris 3 Lehner~ Hansen74 Hahn ~ Hahn & Lange're MacGregorT M

Number of extrac-Number FA tionsor of FA in % surgical removals 6,403 23,886 5,500 4,310 1,079 3,438 5,964 I 0,199

138 226 116 100 33 93 263 329

2.2 0.9 2.1 2.3 3.1 2.7 4.4 3.2

the number of extractions in the individual areas have not been taken into consideration in the calculation of the percentage occurfence of FA. It is more relevant to calculate the frequency of FA within the dental arches (Table 2). The results show that FA is two or three times as frequent after extraction of mandibular teeth as after extraction of maxillary teeth. Apart from single deviations the highest frequency is found

219

after extraction of mandibular molars, especially first and third molars. The average frequency for these two areas is 7.1%, whereas the frequency for the other areas of the jaws is 2.4 % (Table 3). Thus FA occurs three times as frequently after extraction of the mandibular first and third molar as after extraction in the other areas of the jaws TM, o5, ~o2. The much more frequent occurrence of F A in the mandible, and especially in the molar area, can possibly be explained by the etiologic factors, which will be discussed in detail in Chapter 3: "Etiology". Several authors have shown that F A more often occurs after removal of retained teeth % 01,117, l~s, 1.~0. According to most authors the frequency of FA after removal of retained wisdom teeth is about 20%. Only Hansen TM mentions an appreciably lower figure, viz. 5.2 %. His material is too small, however, to allow for decisive conclusions. The reason for the frequent occurrence of FA after removal of retai~aed teeth is stated to be the increased trauma during removal. This is claimed to be an etiological factor in FA (see also Chapter 3).

Table 2. Frequency of fibrinolytic alveolitis (FA) in percent inside the jaws Author

3

11

Lehner95

0.6

1.6

2.8

2.1

2.0

7.4

0.9 [ 2.8

3.2

Author

112

3

Mandible 4 5

0.0

0.0

1.4

0.0 2.2

Lehner9~ Hansen74 MacGregor1~

0.6

2.0

I

1.6

0.0 0.0

3.4

3.61

Total

1.8 I 0.6 I 2.3

Hansen74 MacGrego: 0~

Maxilla 4 5 1 6 1 7 1 8

1.7

1.5 11.8

6.5

3.6

2.6

2.0

7

8

5.8

3.0

7.1

3.9

5.8

2.8

5.8

4.2

9.5

7.8

8.7

7.6

[6

2.6 Total

220

BIRN

DISTRIBUTION ACCORDING TO S I N G L E A N D M U L T I P L E EXTRACTIONS Some authors state that F A m o r e often occurs after single extractions than after multiple extractions3, ~1, xo~ However, M a c G r e gor ~~ has shown that in his material other factors (distribution o f extraction within the arches and age distribution) were present in the groups o f single and multiple extractions in such a w a y that these factors had a tendency to r e d u c e the n u m b e r of cases of F A in the group of multiple extractions. F u r thermore, he points o u t that any direct comparison between the two groups is h a r d l y possible, because patients who allow their teeth to fall into d e c a y to such an extent that m u l t i p l e extractions are necessary possibly have a more robust attitude towards pain, which is the most outstanding symptom in F A a n d therefore the most frequent reason w h y t h e patients seek a dentist for treatment.

SEASONAL VARIATIONS Adkisson & Harris z find that there is a seasonal variation in the occurrence of F A and that this is congruous with the seasonal variation of colds. Other authors deny thisT~, 72, 9~. T h e explanation o f the different opinions of seasonal variations m a y be sought in the climatic conditions in the place where the material originates. T h e investigation by A d kisson & H a r r i s 8 was carried out in Alaska, whereas the material o f H a h n 71 and Hahn & Lange r~ is f r o m G e r m a n y and that of K r o g h from Washington,1.

ONSET AND DURATION F A starts within the first 4 d after extraction ~, ~4, ~1 a n d within a week between 95 and 100 % o f all cases of F A have been registeredZ, 9~. T h e duration m a y vary to some

degree, dependent on the severity of the disease, but is normally stated to be f r o m 7 to 14 d a, a2, 01, ~70 T h e longest d u r a t i o n of F A is possibly one of the cases r e p o r t e d by Crawford 47, which lasted f o r 12 months.

NORMAL HEALING OF EXTRACTION WOUNDS To understand the pathogenesis of F A a brief reference to the n o r m a l healing of extraction wounds is necessary. Investigations into the healing of extraction wounds are carried out primarily on experimental animals44, 80, so, s4, s~, xzs, 152_154. A few investigations have been carried out on homo, t0042,107 ass. Nearly all these investigations are characterized by the difficulty in obtaining a material which completely covers the healing period. However, they have shown that the healing stages in animals and homo are similar, and therefore a p p l y i n g conclusions from animals to homo concerning the succession and number of stages is permissible. On the other hand, investigations have shown that the temporal extent of the stages is different in animals a n d homo, as the extraction w o u n d in the l a t t e r heals considerably more slowly. Thus, it m a y be difficult to date the stages exactly, b u t the w o r k of Mangos ~~ in particular has given a fairly good insight into the d u r a t i o n of the healing stages. A few minutes after extraction the alveolus will fill with blood. Simultaneously, an intravascular co~igulation, which clogs up the torn vessels i in the periodontal m e m brane and the adjacent m a r r o w spaces, and a clotting of the blood in the alveoIus will take place. Within the first 24 h this clot will consolidate by network p o l y m e r i z a t i o n of the fibrin fibers formed. This will cause shrinkage of the clot. In this way it m a y be detached from the alveolar wall; b u t the marginal gingiva will simultaneously fold over the extraction wound and thus keep in

ETIOLOGY AND PATI-IOGENESIS OF FIBRINOLYTIC ALVEOL[TIS contact with the clot and prevent the occurrence of a cleft with communication to the oral cavity96,144. In the same period the clot will be infiltrated by leukoeytes, especially polymorphonuclear, and also a slight inflammatory reaction will be seen in the adjacent marrow spaces concentrated around the vessels. Gradually the inflammatory cells of the clot will converge on its surface, which may eventually be completely covered by these cellsS~176155. Within 3 d the inflammatory reaction will abate and be replaced by proliferative processes in which capillaries and young fibroblasts will invade the clot. The formation of this granulation tissue is most active in the marginal and apical third of the alveolusC0,T0,107,155.Which areas originate the granulation tissue formation is still undecided. Some authors t07, 162, 155 are of the opinion that the remainder of the periodontal membrane does not participate in the formation of granulation tissue, but rather undergoes hyaline degeneration. The ingrowth then takes place exclusively from the perforations in the lamina dura. OthersT,,s0,8~,s~ state that the periodontal membrane stays vital and participates in the formation of granulation tissue. But this is only so where perforations of the lamina dura adjoin the membrane. Within a week, incipient osteoclastic activity will be seen in the adjacent marrow spaces and along the lamina dura 1~ It is interesting that several investigations show that the inflammatory process as well as the osteoclastic and osteoblastic activities are not limited to the tlearest surroundings of the alveolus, but take place in the marrow space all over the alveolar process, and involve the periosteum as wel135,s4, sS. Ten days after extraction, osteoblastic activity will be seen in the marrow spaces as well as in the alveolus itself. Subsequently a maturing of the connective tissue and a filling of the alveolus with bone tissue will take place. This process will last for 2 or 3 months, ac-

221

companied by a constant rebuilding of already formed bone tissue x~ After 3 d incipient proliferation of the gingival epithelium over the wound will be seenl~ The epithelium will normally cover the wound completely after 14 daysl~ This is an important phase in the healing as the complete epithelialization ensures against exogenously determined complications.

H E A L I N G IN F I B R I N O L Y T I C ALVEOLITIS Investigations into the healing process in F A have been carried out on experimental animals only, where F A has been produced experimentallylO 44,11~. Meyer118 and Claflin 44 used dogs as experimental animals. T h e former tried in several ways to disturb the normal healing (insertion of foreign bodies, plugging, and infection). F A could be produced only when pure cultures of streptoand staphylococci were placed deep in the alveolus with an inoculation needle. Claflin 44 placed a plug saturated with a mixed culture of the same bacteria in the alveolus. Both procedures seem to be rather violent and can hardly be compared with the circumstances under which F A normally develops in homo. It should be mentioned, however, that Claflin 44 registered spontaneously developing F A in his experimental animals. These cases of F A showed the same histologic picture and healing as the experimentally produced cases. All investigations show the same course. After 1 to 3 d complete or partial disintegration of the blood clot is seen. If remains of the blood clot are found, they are heavily infiltrated with inflammatory cells and show signs of disintegration. Large areas of the lamina dura are necrotic with empty osteocyte lacunae in the bone tissue. The inflammatory process has spread into the surrounding marrow spaces and often into the periosteum. The gingiva shows a heavy subepithelial inflammation.

222

BIRN

Necrotic tissue is often found in the marrow spaces closest to the alveolus. The histologic picture is typical for an acute or subacute osteomyelitis with thrombosed vessels and violent infiltration by polymorphonuclear and mononuclear leukocytes in the marrow spaces. Because of the violent inflammatory reaction the reparative processes start late and are preceded by extensive osteoclastic activity, which sometimes causes sequester formation. At varying times after the extraction, granulation tissue starts to grow into the alveolus through the perforations of the lamina dura. The alveolus is gradually filled up from the bottom with granulation tissue, and at the same time the epithelialization starts. After the alveolus has been filled with granulation tissue and covered by epithelium the healing takes its normal course.

PAIN A N D F I B R I N O L Y T I C ALVEOLITIS The violent, neuralgjform pain which always accompanies F A has been explained in several ways. Some authors consider the pain to be caused by unmyelinated nerve ends, which during the disintegration of the blood clot are unprotected and exposed to irritation from bacteria, breakdown products, and food debris~, ,6, ~2.~,128,181,143,170. In view of the fact that nerve tissue is extremely sensitive to changes in the environment and rapidly dies under unphysiologic influence, it seems unlikely that functioning nerve fibers should be present in the empty alveolus

in FA. Other authors have stated a neuritis to be the cause of the pain in FA. This neuritis is believed to arise because the infection of the alveolus spreads into large nerve trunks, e.g. the inferior alveolar nerve s~. However, this theory does not explain the outbreak of pain in areas where nerve trunks do not exist. Finally, trauma to the sympathetic nervous system has been stated to be the cause of pain. This trauma gives rise to vascular contraction and, with that, pain 41. Although Chalifour 41 obtains painlessness in F A by periarterial injection of local anesthetics, the explanation of this is probably to be searched for in some condition other than blocking of the sympathetic nervous system. It does not seem resonable to suppose that an ischemia in the surroundings of the alveolus should exist during the total period of F A in which pain is present.

CONCLUSION

Due to the present state of our knowledge, it is not possible to satisfactorily explain a number of the clinical characteristics of FA. This applies to the age and sex distribution. As will be commented on more fully in Chapter 3: "Etiology", this applies also to the distribution of F A within the dental arches. Furthermore the present knowledge about the pathogenesis is incapable of completely explaining the two most characteristic features in FA: disintegration of the blood clot and the violent pain.

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS

223

CHAPTER 3

Etiology This chapter will cover the statements about the etiology of F A published up till now. T h e etiologic factors can be divided into two m a i n groups: (1) general factors and (2) local factors.

GENERAL FACTORS A lot of general factors have been considered important to the development of FA. Several authors call attention to a decreased resistance in the patient caused by general diseases, e.g. heart diseases, uncontrolled diabetes, liver diseases, syphilis, anemia, hem o r r h a g i c diathesis, disturbances in the function of the endocrine glands and diseases of the sympathetic nervous system ~, 82, 4~, 5~, 84, 75,122, xa~.1~0,181. Other reasons for the decreased resistance in the patient may be nutritional disturbances such as protein deficiencies, vitamin A, B, C and D deficiencies and calcium or phosphorous deficicies18,4n, 75,110 1~2 130 131,150~1581 170.180 However, m a n y authors believe that these general factors are secondary and may predispose to the development of F A if one Or more local factors are presenta~,45, tz0,170. Only two of the authors mentionedl~D,~80 state that they have been able to reduce the incidence of F A after extraction by administering vitamins (vitamin B) and proteins; but they do n o t specify the method used or the exact results of their investigations. On the other hand, in a just as poorly elucidated examination of an unknown number of patients, G a r d n e r ~ was unable to find any

correlation between the occurrence of general diseases or nutritional disturbances and the occurrence of FA. The following investigations are more essential. Erickson, Waite & Wilkison59 in a material of 98 patients found no relation between the occurrence of F A and the general health of the patients. Likewise, MacGregor 1~ in a material of 3,983 patients did not find that the occurrence of F A is significantly more frequent in patients with a "not normal general health". Thus, the stated correlation between general diseases and the occurrence of FA seems to rest chiefly on a speculative foundation and does not find support in the present, wellproved investigations. Most authors base their theory of such a correlation on the well-known experience that the above-mentioned diseases or nutritional disturbances generally delay healing and increase the risk of complications in any surgical intervention. Therefore, one cannot immediately exclude the possibility that they are of some, a/though minor importance in a few cases of FA. Most of these diseases are rare in comparison with FA, and furthermore are so serious that extraction would hardly be performed without special precautions and attempts to bring the patient to normal physical condition. Other circumstances, too, point to the fact that general factors do not play any noticeable part in the development of FA. If that was the case, one should suppose that multiple extractions in a patient with a general, predisposing disease would give rise to development of F A in all

224

BIRN

extraction wounds. However, this occurs very rarely. Conclusion - The importance of general factors in the development of F A must be concluded to be highly doubtful, and decisive in only a very few cases. LOCAL FACTORS Most authors incline to the opinion that local factors are responsible for the development of FA. Here, too, many factors have been mentioned: 1. Insufficient blood supply to the alveolus. 2. Pre-existing infection (apical granuloma, marginal periodontitis, pericoronitis). 3. The use of too large amounts of local anesthetics with vascoconstrietor. 4. Postoperative bleeding. 5. Trauma to the alveolar bone during extraction. 6. Infection during or after the extraction caused by e.g. entrance of saliva or use of unsterile instruments. 7. Root or bone fragments or foreign bodies left in the alveolus. 8. Excessive irrigation or currettage after extraction. 9. Fibrinolytic or proteolytie activity in the blood clot. Insufficient blood supply to the alveolus

Two reasons for an insufficient blood supply to the alveolus have been put forward: It could either be caused b f the normal anatomical structure of the alveolar bone and its nearest surrounding bone or by a pathologically determined change of the structure of the alveolar bone. Several authors state that the reason for the frequent occurrence of F A in the molar area of the mandible is the insufficient blood supply caused by the heavy layer of solid bone which surrounds the roots of these teeth and contains few vessels~5, 69, 79, 95~109~117j 126,137,140~ 156 AS a

confirmation of this theory, Lehner 95 emphasizes that F A is hardly ever seen before the age of 18, i.e. during t h e period when the blood supply in general is abundant. But none of the above-mentioned authors have investigated the blood supply to the alveolus in the different areas of the jaws. Most of them refer to general anatomical observations concerning the distribution of solid bone in the jaws. However, Huebsch ~9 has shown that the healing of the alveolus in rats is quicker if artificial perforations are made in the alveolar wall. But this does not prove that the healing is not quick enough under normal conditions. Investigations of the blood supply to the alveoli have been carried out by Hay~shW by injecting Prussian blue into the carbtids. H a y a s h W showed that the blood supply to the alveoli decreased from one group of teeth to the next in a posterior direction, but increased within each group of teeth except for the incisors of the mandible. Thus, his investigation confirms the assumption that the blood supply to the alveoli of the molars is poorer than that to the other alveoli in the same jaw. F r o m his description, however, it is not possible to make a comparison between the blood supply to alveoli in t h e maxilla and mandible. Though the investigation by HayashW is thorough, it is restricted to a single subject and makes use of an inexact method in which differences in the blood supply are only estimated. Therefore, the investigation is not supported to an extent that would allow one to conclude that less blood is supplied to the alveoli of the molars than to other alveoli. Sclerotic bone changes caused by periapical infection should also b e able to create decreased blood supply to the alveolusis, ~4, ~0, 05,112,131, 156,181. The only author who tries to substantiate this theory is Lehner 95. He found 20 cases of F A in patients with sclerotic or thickened lamina dura around the alveolus in a material consisting of about

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITI8 2,500 extractions. In 31 other cases of FA no pathologic changes could be observed on radiographs. He does not mention how m a n y cases of sclerosing osteitis occurred in the total material. When comparing the above-mentioned figures it does not seem immediately intelligible that from this Lehner g5 concludes that sclerosing osteitis is an etiologic factor in FA. On the other hand, some authors 15,91 have shown that FA develops far more often after extraction of vital teeth than after extraction of teeth with a necrotic or inflamed pulp, with the consequent possibility that periapical inflammations and bone changes will develop. Whether periapieal infections really were present in their materials cannot be ascertained as no radiographs of the extracted teeth are available. Krogh 91 thus found that retained teeth with vital pulps develop FA in 18.6 % of all cases, whereas erupted teeth, which are often extracted because of periapical processes, show a frequency of 1.2 %. In an analysis of 226 cases of F A after 23,886 extractions Archela~ found that 62 % of FA occurred after extraction of vital teeth and 3 8 % after extraction of non-vital teeth. Finally it should be mentioned that MacGregor 1~ found that in 3,080 extractions of teeth with pulpitis, 159 (5.2 %) developed FA, whereas the extraction of 921 teeth without pulpitis gave rise to 41 cases of F A (4.5 %). But MacGregor 1~ does not believe that this difference justifies the theory of a relationship between F A and pulpitis. C o n c l u s i o n - Although there is orlly weak evidence of insufficient blood supply caused by the normal anatomical structure around the alveoli of the mandibular molars and no evidence of any connection between FA and insufficient blood supply, this etiologic factor can hardly be excluded. On the other hand, there does not seem to be any basis for the assumption that pathologic changes of the alveolar bone should be responsible for the development of FA.

225

P r e - e x i s t i n g injection

Several authors have emphasized that periapical or marginal infections may cause infection in the alveolus and the blood clot, thus giving rise to the development of FA 46, 71, Sll, 122, lS0~ 131,142, 1511,170,180. But none of the above-mentioned authors have carried out any investigations which substantiate this assertion. For periapical infections as the cause of FA see the argumentation concerning this possibility in the passage "Insufficient blood supply to the alveolus" on p. 224. From this it appears that there is no reason to suppose that periapical infections and resulting sclerosing bone changes are the cause of FA. In an investigation into the cause of healing disturbances (FA) Hahn&Lange 72 found that of 210 cases, 16 were caused by pulpiris and 15 by acute periapical infection, whereas 46 were caused by gingivitis and marginal periodontitis resulting from poor oral hygiene. This means that about onethird of all cases of FA are caused by preexisting infections. The question is, however, how valid the stated figures are, as prolonged extraction and bite lesions of the wound are also mentioned as causes of healing disturbances. It seems difficult to isolate these factors unambiguously so that they can be weighed against the above-mentioned factors. It has been shown definitely that extraction of teeth with pericoronitis gives rise to a substantial increase in the number of cases of FA. Thus Kay s7 found that FA develops in 24 % of all cases with pericoronitis. In this connection it did not matter whether it was an acute or chronic infection. But the incidence of FA was much higher (88 %) when the pericoronitis had spread into the bone ("deep pocket" cases). Rud x'~s also found a high incidence of FA in pericoronitis, J.e. 31% in acute infection and 20 % in chronic infections. Adkisson & Harris 3, too, found a considerable increase in the fre-

226

B1RN

quency of FA in cases with pericoronitis. By way of comparison it may be mentioned that in a material selected without regard to pericoronitis, MacGregor lo~ found that the incidence of F A in mandibular third molars was about 6 %. Lehner ~ found that F A develops after about 7 % of all extractions of mandibular third molars. 0 n l y a few cases of perieoronitis were found. All authors agree that the increase in the incidence of FA is caused by the presence of infection which spreads into the alveolar bone and the blood clot. C o n c l u s i o n - There seems to be no basis for the assertion that periapical or marginal infections are an essential cause of FA if these infections do not spread or exacerbate in connection with the extraction. It seems that rather violent and extensive infections are necessary for FA to develop. Thus perieoronitis seems to be an infection of sufficient extent to cause F A by spreading into the bone marrow and blood clot. L o c a l a n e s t h e t i c s wittl v a s o c o n s t r i c t o r

It has been mentioned, but not conclusively proved, that when local anesthetics with vasoconstrictor are used there is a possibility of producing ischemia in the alveolar bone, resulting in decreased bleeding and missing clot formation. This may cause the development of F A ae, aT, 45, 75, 7a s6, on, ~=2,lz2, a49,xv0. Only Lehner 95 has made a direct investigation into the influence of local anesthesia on the number of cases of FA. He found that the incidence of FA is twice as high when infiltration anesthesia is used as occurs with general anesthesia. However, only a slight increase in the incidence of F A is seen when block anesthesia has been used. From this he concluded that infiltration anesthesia gives rise to a temporary ischemia followed by a poor blood supply to the alveolus. A number of authors are of a different opinion, however. Thus Krogh 91 emphasizes from his own investigations that the incidence of F A is by far the highest in the

mandibular molar area, where block anesthesia is used. This means that factors other than the ischemia-producing properties of local anesthetics must be responsible for the development of FA. Rud ~3~ found that the incidence of F A does not increase with the use of local anesthesia instead of general anesthesia in connection with removal of mandibular third molars with pericoronitis. Kay sr found only an insignificant increase when using local anesthesia instead of general analgesia in removing impacted third molars with pericoronitis. H e ascribed this increase to other factors (the operation technique) than the anesthetic. Meyer ~5 arrived at a similar conclusion. H a h n 71 and Schilli et alYa2 found an equal n u m b e r of cases of F A using local anesthetics either with or without vasoconstrictor. Thus m a n y investigations show that the use of local anesthetics with vasoconstrictor is of no importance in the development of FA. Besides, it must be stressed that the vast majority of cases of F A occur by disintegration of a normally produced clot, and only a minority of cases arise because of lack of bleeding to fill up the alveolus% 37 % 79,108. Thus non-filling of the alveolus with blood, which might be caused by ischemia after local anesthesia, does n o t seem to be of importance to the development of FA. As the ischemia lasts for 1 or 2 h only and is followed b y a reactive hyperemia, it is of no importance to the subsequent disintegration of the blood clot, either. C o n c l u s i o n - Thus it must be concluded that the use of local anesthetics with vasoconstrictor has not been proved to be of any importance in the development of FA. Postoperative bleeding

A few authors consider this complication to be the cause of FA4~, 7~, b u t none of the above-mentioned authors have carried out any investigations which substantiate the theory that development of F A is more Ire-

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS quent after extractions with postoperative bleeding. Nor is it immediately intelligible why a disease which is characterized by a missing blood clot should occur where bleeding is more vigorous than normal. Thus McIntyre, Nour-Eldin, Israels & Wilkinson ~lx and McIntyre 1~o do not mention one single case of F A in connection with extraction of from 1 to 24 teeth in 164 patients with increased tendency towards bleeding. However, if the bleeding is caused by violent trauma to the tissue, complications may arise, but in this case the cause should be grouped with trauma rather than postoperative bleeding. C o n c l u s i o n - P o s t o p e r a t i v e bleeding is not likely to be the cause of FA. T r a u m a to the alveolar bone

Some authors are of the opinion that trauma is the main cause of F A 59, Gr,74, 91, ~0~,12% 141, lsl. Thus Krogh 9~ found in a material consisting of 6,403 extractions that the number of cases of F A in so-called "easy extractions" was 0.7 %, but 23.5 % in "difficult extractions". Erickson et al. 50 found that 1.5 % of F A occurred after simple extractions, whereas 60.4% occurred after complicated surgical interventions with flap raising and bone resection. Hansen TM found that after removal of 1,079 teeth F A occurred in 2 % of the cases of simple extractions but in 7.3 % of the cases of surgical removal. MacGregor ~~ showed that the number of cases of F A in 10,199 extractions rose from 3.3 % in non-difficult extractions to 10.3 % in extractions with complications (fractured roots). Finally, Ailing & Kerr 1~ could produce F A on rhesus monkeys by injuring the alveolus with a metallic instrument. F r o m this they conclude that trauma is the cause of FA. Thus there is a series of investigations which clearly show that F A occurs far more often after particularly injurious extractions or operative procedures (between 60 % and

227

99 % of all cases of FA occur after surgical interventions in which the, trauma is greater than normal). On the other hand, some authors believe their results to show that F A has no relation to trauma. Archer~ found that trauma was present in only 56 % of the cases of F A after extraction of 23,886 teeth, the average incidence of FA being 0.9 %. F r o m this he concluded that trauma is hardly a decisive factor. However, it seems difficult to understand that extractions can be performed without it being true that "trauma is at hand". Furthermore, the percentage mentioned does not seem small enough to justify the conclusion. Adkisson & Harris3 drew the same conclusion after investigating 5,000 extractions. After removal of 47 third molars S w a n s o n ~ found that in cases of minimal trauma the incidence of F A was 62.5 % and in cases of considerable trauma it was 28.6 %. F r o m this he concluded that trauma has no influence on the occurrence of FA. However, the number of patients in the groups "minimal" and "considerable" trauma is small (8 and 7 patients, respectively), and no reliable conclusion can therefore be drawn. Finally should be mentioned the many emphases on the clinical experience that F A sometimes develops after very easy extractions in which the trauma has been minimal, and it is probable that just these cases will be remembered when the foundation of experience is recapitulated in the memory. However, the investigations that confirm the influence of trauma on the development of F A are the more weighty. The material investigated by Swanson~50 is small, and the conclusions of both Archer ~5 and Adkisson & Harris8 are not immediately inteUigible from the figures stated. Conclusion - F r o m the present investigations there seems to be no doubt that trauma is if not the only, at any rate an important cause of the development of FA.

228

BIRN

Infection o! the alveolus Several authors have stated infection to be the cause of FA3,16, 27, 87, 89, 48, "/1-78, 80, Oil, 1~ xzi, 14~-14s,159. Thus HahnTX reduced the number of cases of F A from 4 . 4 % to 1.5% by thoroughly cleaning the tooth and its surroundings before extraction. Hahn & Lange TM obtained a reduction in the number of F A from 4.4 % to 3.2 % after a similarly thorough preoperative treatment. Chudzinskia8 found an F A frequency of 3.1% when using a strictly aseptic technique in operative removal of mandibular third molars. In an ordinary surgical procedure the frequency was 10.3 %. But the material was not large enough to verify the significance of the difference stated. TilP 82 put the patients on a diet, the purpose of which was to avoid nutrients for anaerobic bacteria (proteins) and sticky foods such as flour and sugar. I n 914 patients on this diet only one case of F A developed. But the methods used in these investigations do not exclude the possibility that other factors, too, were of importance in the reduction of FA. These could be a difference in the thoroughness during extraction or operation and temporal variations, as simultaneity in obtaining experimental and control material is not present in any of the investigations. Schroff & Barrels 14s consistently found fusobacteria and spirochetes in the alveolus of eight patients with F A and think that this gives a hint of the etiology in FA. Archer 1~ found streptococci in 80 % of 226 cases of F A in 23,886 extractions. He believes that these bacteria are the cause of this complication. In 84 patients, 11 of whom developed FA, Brown et al. 30 found that the number of microorganisms pre- and postoperatively, in the wound as well as in saliva, was significantly higher in patients who developed FA. The bacteria in question were especially streptococci including the 15-hemolytic ones. They concluded that patients with a preoperatively high number of bacteria have a

greater tendency towards developing F A . But they did not consider this conclusion definitive of the etiology of F A . Meyer 116 could produce F A experimentally on dogs by placing a pure culture of streptococci and staphylococci in the alveolus. Claflin 44 showed that delayed wound healing can be produced experimentally in dogs by inserting a gauze strip saturated with a mixed culture of streptococci and staphylococci into the alveolus. However, it is questionable whether such a substantial contamination with bacteria can be compared with the conditions under which F A normally develops. In any case, the high number of cases of F A which develop after removal of semiretained third molars with pericoronitis confirm that infection is of importance in the development of FAn, sT, la0. This also applies to the well-substantiated reduction in the number of cases of F A in local antibiotic therapyS7, 46, 73, 70, 92, 0e, lt7,184, is0, ~40,l/f0. On the other hand, it has been stated that infection does not play any part in the development of F A 10, cs, 95,10s-10~. GrandstaffGs carried out bacteriologic investigations of 40 extraction wounds and did not find any differences in type of bacteria in normally healing alveoli and FA. M a c G r e g o r t0s and M a c Gregor & H a r t x04' ~0~ have carried out extensive and well supported investigations on types and number of bacteria in extraction wounds with normal healing as well as F A . They found no significant differences, either qualitatively or quantitatively, in the bacteria of the two groups, and concluded from this that infection is not an etiologic factor in the development of FA. In this connection the bacteria must be regarded as saprophytes. Finally, Rovin, Costich, Flemming & Gordon ~88 have shown that the healing of extraction wounds takes place without essential differences in germ free and normal mice. The inflammatory reaction was the

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS same, if minor differences caused by the degree of trauma were disregarded. Conclusion - In defiance of the contradictory findings it must be concluded that infection is undoubtedly of importance in the development of FA. But also other factors influence. This combination of several factors may, dependent on the statement of problems and what is demanded of the resuits, to a more or less pronounced degree conceal the importance of a single factor. Remaining root or bone fragments or foreign bodies in the alveolus A few authors especially emphasize this complication as the cause of FA45,~, m. There can hardly be any doubt that if root or bone fragments or foreign bodies (e.g. amalgam) are present to a great extent, they m a y give rise to complications, including F A , inasmuch as they are the manifestation of a particularly traumatic extraction or cause infection of the alveolus. But by histologic examination of the healing of extraction wounds in monkeys Simpson~5~-~5 has shown that to the extent they are found after normal extraction or surgical removal of teeth, small bone and tooth remnants do not cause complication during the healing. Conclusion - Remaining root or bone fragments or foreign bodies are in themselves hardly capable of causing FA. Only if they give rise to infection or are the manifestation of a particularly traumatic extraction, F A may sometimes develop. Excessive irrigation or currettage of the alveolus after extraction A few authors have put forward these causes of FAU, 171,is0 None of the above-mentioned authors have carried out any investigafigns which confirm their assumptions, but it seems resonable to suppose that energetic, repeated irrigations of the alveolus might interfere with the clot formation and gNe rise to infection. Likewise, violent currettage

229

might injure the alveolar bone. However, it is doubtful whether these excessive procedures, both of which normally serve a distinctive aim, are carried out to such an extent that the development of all eases of F A can be explained in that way. Heavy sucking or spitting postoperatively Heavy sucking or spitting postoperatively is reported to result in the detachment of the blood clot from the alveolus and the consequent development of FA6~. Even other injuring treatments of the wound (e.g. irritation by the tongue or toothpicks) have been attributed with causing FAS4. Gardnera~ claims to have carried out an investigation which showed that sucking and spitting postoperatively were the only causes of FA. But the extent and method of the investigation are not stated, and in the work which is recorded there seems to be no basis for the factors mentioned to play any part in the development of F A . Increased fibrinolytic or proteolytic activity in the blood clot This cause of F A has been emphasized by Sinclair 150. Later reports by other authors have also mentioned increased fibrinolytic activity as a possible etiologic factor in FA~a, ~, 142,145,147,14s, 160. The authors trace the fibrinolytic activity back to the saliva, originating either from its bacteria and cells or from secretions of the salivary glands. However, none of the above-mentioned authors have shown any direct connection between F A and fibrinolytic activity, although Schulte & Gewalt146 found that in six patients with disturbances in healing after extraction the fibrinolytic activity in saliva was considerably higher after than before the extraction. Finally, Doku, Shklar & Bugbee 40 have found that the healing of extraction wounds in hamsters is promoted by local application of epsilon-amino-caproic acid, which restrains the fibrinolytie system.

230

BIRN

Conclusion - Although a connection between Iibrinolytic activity and F A has not at all been proved, this possibility cannot be excluded, particularly considering the fact that the most outstanding clinical feature is lysis of the blood clot.

CONCLUSION A N D S T A T E M E N T OF PROBLEMS A critical interpretation of the many local factors suggested as causes of F A shows that for some of them there is no basis for assuming that they are of any real importance in the development of this disease. This applies to: 1. Pre-existing infection in the form of periapical or marginal infections. 2. The use of too large amounts of local anesthetics with vasoconstrictor. 3. Postoperative bleedings. As for other suggestions as to the etiology there is sufficient evidence - although not unambiguous - that each of them is an essential, but not exclusive etiologic factor in FA. This applies to: 1. Trauma to the alveolar bone during extraction. 2. Infection provoked during or after the extraction. Furthermore, it applies to two of the suggested etiologic factors that they seem resonable but are not sufficiently proved:

1. Insufficient blood supply to the alveolus. 2. Increased fibrinolytic activity in the blood clot. Finally, a possible importance of some of the suggested etiologic factors may be classed with trauma or infection: 1. Remaining root or bone fragments in the alveolus. 2. Excessive irrigation or currettage of the alveolus after extraction. 3. Pericoronitis. 4. H e a v y sucking and spitting postoperatively. Therefore, the only etiologic factors it seems reasonable to subject to a closer examination are: 1. Insufficient blood supply to the alveolus. 2. Increased fibrinolytic activity in the blood clot. 3. Infection during or after the extraction. 4. T r a u m a to the alveolar bone during extraction. This conclusion, related to the insufficient explanations of some aspects of the clinical picture and pathogenesis as mentioned in Chapter 2, is the basis for the present thesis. The aim has been to find an etiology and pathogenesis which will be in harmony with the well-established knowledge of F A and at the same time will give a more certain knowledge of the theories and hypotheses so far insufficiently substantiated.

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS

231

CHAPTER 4

Blood supply to the alveoli As emphasized in Chapter 3 insufficient blood supply to the alveolus is considered a possible cause of F A . The connection between the high incidence of F A in the mandibular molar region and the heavy layer of solid bone in this area, which is believed to cause poor blood supply to the alveoli, has especially been stressed. This theory seems to be substantiated by the investigation into the blood supply to the alveoli by Hayashi 77. F r o m this it appears that the blood supply decreases in the posterior part of the row of teeth. It should be noted that the information in Article I incorrectly states the opposite about the work of HayashiTt Unfortunately, this was ascertained only after a review of the most abstruse work. However, for the reasons mentioned in Chapter 3 the investigation by HayashiTr has some shortcomings which make it difficult or impossible to draw any certain conclusions concerning the blood supply to the different alveoli. Therefore the investigation referred to in Article I was carried out. The material consisted of 84 alveoli in Indian crania evenly distributed on the seven first teeth in the maxillary and mandibular quadrants. By a special impression technique polyvinyl-chloride copies of the alveolar walls were made. These copies were drawn on paper under a stereomicroscope. By the so-called measureand-weigh method the area of the alveolar wall as well as the area of the perforations in lamina dura could be calculated. Besides, the perforations in lamina dura were count-

ed and divided into large ( > 150 gm) and small ( ~ 150 ~tm) perforations. Finally, the relationship between the perforations in lamina dura and the vessels running through the perforations was examined on five rats. The vessels of the rats were injected with India ink and the rats then sacrificed. Serial sections perpendicular to the long axis of the alveoli were made and the width of the perforations and their vessels transferred to paper to make a graphic reconstruction of the alveolar wall and its perforations and vessels (Article I). This investigation showed that there is a direct connection between the number and size of the perforations in lamina dura and the number and size of the vessels which run through the perforations to the alveolus. This connection was considered so fundamental that it must be expected to exist in homo, too. The results of the investigation clearly show that the blood supply increases evenly in a posterior direction in the row of teeth and is greatest in the area of the mandibular and maxillary second molar. This increase is significant at the 0.1% level (F = 7.9808; n 1 = 13; n~ = 70) (Fig. 1). There is no substantial difference between the blood supply to alveoli in the maxilla and the corresponding ones in the mandible. Furthermore, it was shown that the increase in blood supply in a posterior direction is characteristic for all surfaces of the alveolus (Fig. 2) (significant at the 0.1% level, as F=189.8750; n i = 1 3 ; n.9---70). Even the buccal surface of the alveolus shows an increase in the area of perforations

232

BIRN

MAXILLA

7 5 4 3 2 1 +

0.040 0.060

0,020 I

I

!

I

~

~

0.080 i

-

t

0.100 I

I

i

'

O.120 r

#

i 0.140

I

I

MANDIBLE

Fig. 1. Mean area of perforations per unit surface area of the alveolar wall in the entire alve61us of the different teeth. Analysis of variance of the logarithmic values gave a significant Fvalue (observations logarithmically normally distributed). The bar chart shows that the mean area of perforations per unit area of the alveolar wail increases evenly posteriorly in the jaws to reach its maximum corresponding to the maxillary and mandibular second molar.

per mm2 in the molar area of the mandible, where the buccal layer of solid bone increases extremely in thickness. So, there seems to be no relationship between the thickness of the outer layer of solid bone and the blood supply to the alveolar walls. On the contrary, the investigation seems to show that in areas where t h e alveolar wall is thin ~nd contains only a sparse amount of bone rharrow, the blood supply is smallest. This i$ seen when comparing the blood supply to the alveoli of the incisors with that to the alveoli of the molars (Fig. 2). The third molar was not incorporated into the invest-

igation, but it seems reasonable to suppose that the evident tendency for a better blood supply the m o r e posteriorly the alveolus is situated applies to the third molar, too. A n y way, the theory that insufficient blood supply is the cause of F A cannot be valid for the m a n d i b u l a r first and second molars, where a considerable number of all cases of F A are found. The alveoli of the molars have a much richer blood supply than the alveoli o f the incisors, where, as previously mentioned, F A hardly ever occurs. The age distribution within the material was unknown. But as only alveoli with no or only minimal bone resorption were used, one must assume that the material consisted of rather young individuals - considering the widespread occurrence of marginal periodontitis among the Indian population. I t is likely, though, that the material falls within the age group where F A is most frequent (20-40 years). Thus, in a radiographic investigation of the periodontal conditions in 568 persons between 9 and 60 years of age, D a y & Shourie a8 showed that a superficial bone resorption like the one accepted in the present investigation (Article I) is common in Indians between 20 and 30 years of age. Besides, it must b e assumed that even if increasing age causes a general decrease in blood supply, this will be evenly distributed within t h e jaws and in this way n o t affect the conditions shown, As a relationship between the size and number of vessels running through the perforations and the size and number of the perforations themselves was shown in rats only, the validity of a similar correlation in homo m a y be contested. However, it is questionable whether these rather large vessels in the perforations have any distinct influence on the ingrowth of granulation tissue into the alveolus during healing. The fact is that it appears from the time of onset of F A a n d the histologic investigations into normal healing of alveoli (see p. 220) that

ETIOLOGY AND PA'I~OGEiNESIS OF FIBRINOLYTIC ALVEOLITIS MAXILLA

0.020 t

I

0.040 i

I

0.060 t

I

0.080 i

f

0300 =

#

O.120 r

I

0340 t

I

O.160 r

I

O,180 .

I

.

this ingrowth might be the decisive factor in whether F A occurs or not. Compared to this, and as previously mentioned, the primary filling of the alveolus with blood, in which the above-mentioned vessels most certainly are of importance, is not an essential factor in the development of FA. The possibilities of formation of granulation tissue in the alveolus a r e more likely dependent directly on the area of connective tissue present in the alveolar wall, i.e. in the perforations of the lamina dura. This is substantiated by the observation that the ingrowth of granulation tissue into the alveolus happens most rapidly where the number and size of the perforations are largest: in the marginal and apical part of the alveolus (Article I). Thus the discussion about the importance of an insufficient blood supp l y in the development of F A should rather be a discussion about an insufficient area of connective tissue in the alveolus. In the investigation reported (Article I), this area of connective tissue has been proved with certainty to be largest in the posteriorly situated alveoli. C o n c l u s i o n - T h e investigation referred to (Article I) seems to show that insufficient blood supply, or maybe more accurately, too small an area of connective tissue, for the formation of granulation tissue cannot be the cause of F A as there is an inverse proportionality between the anatomic distribution of perforations in the lamina dura

Mean area of perforations per unit surface area of the alveolar wall in the mesial, buccal, distal, and oral surfaces of the alveolus of the different teeth. Analysis of variance of the logarithmic values for the individual surfaces gave a significant F-value (observations logarithmically normally distributed). It is shown that even in the buccal surfaces of the alveoli of the mandibular molars, where the solid layer of bone is particularly heavy, the area of perforations increases corresponding to increasing thickness of the solid layer of bone. Fig. 2.

MANDIBLE

: MESIAL SURFACES

~

: FACIAL SURFACES

B B : ORAL SURFACES

: DISTAL SURFACES

233

234

BIRN

with possibility of ingrowth of granulation tissue and the distribution of FA. Thus, the etiologic factors left which are of importance in the development of F A are:

1. Increased fibrinolytic activity in the blood clot. 2. Infection during or after tooth extraction. 3. Trauma to the alveolar bone during extraction.

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS

235

CHAPTER 5

Fibrinolysis GENERAL ASPECTS A most copious survey of the development of our knowledge of fibrinolysis, the factors involved, and its importance under normal as well as pathologic conditions has been given by Konttinen s~ and Astrup 21. Therefore only relations of special importance to the understanding of the fibrinolytic activity in connection with F A will be discussed in this chapter. It has been known for a long time that post-mortern blood became fluid and that blood incubated with various agents such as alcohol, ether and chloroform gave rise to fibrinolytic activity21, so. Tillett & G a r d n e r ~64 in filtrate of cultures of hemolytic streptococci found an agent that could cause rapid fibrinolysis of human blood clot. Later investigations 16~ showed that especially the [5-hemolytic streptococci belonging to group A were fibrinolyticaIly active. T h e fibrinolytic activity was especially pronounced in human blood, but weak or missing in blood from other mammals. On the basis of a missing effect of filtrate of streptococci on fibrin but pronounced fibrinolysis by adding small amounts of the euglobulin fraction, MilstoneH8 supposed that a precursor of the fibrinolytically active agent was present in human blood. The fibrinolytically active agent was formed from the precursor by the action on filtrate of streptococci. A similar conclusion was drawn on the basis of investigations into the fibrinolytie activity in tissue extracts~a, 24 and tissue

fluids 6, I n the latter investigation activators were found which directly affected the formation of fibrinolysin. On the basis of these observations and a lot of others it is possible today to arrange a diagram of the fibrinolytic activity in the organism as shown in Fig. 3. This diagram will be further commented on in the following. There is some doubt as to the existence of a proactivator in human blood. T h e theory of the existence of a proactivator was first put forward by Mullertz & Lassen 121. They obtained activation of bovine plasminoge~l by a mixture of streptokinase and h u m a n globulin. The missing proactivator in bovine plasma was therefore believed to be the explanation of the fact that streptokinase cannot activate bovine plasminogen. Other authors have postulated that proactivator does not exist as an independent agent b u t should rather be considered a quality (proactivator activity) caused b y action on human plasminogen by streptokinasel, ss, 15~. However, proactivator activity as a possibility of indirect formation of plasmin will be just the same no matter which theory is correct. As the diagram shown in Fig. 3 has for many years been of extremely practical use as a working model, it will be maintained in the present thesis. Thus, there will be a number of kinases which are capable of forming activator from proactivator. It is partly a question of a number of bacterial kinases, of which streptokinase is the most well-known, and the most potent, too (Article III). But a great

236

BIRN

LYSOKINASES IN BLOOD TISSUE KINASES (LYSOKINASES) STREPTOKINASE

PLASMINOGEN

PROACTIVATOR~ (IN BLOOD)

~

ACTIVATOR" - ~

PLASMIN

ACTWATGIR IN BLOOD UROKINASE TISSUE ACTIVATOR BACTERIAL ACTIVATOR TRYPSIN CHLOROFORM A.O.

~' LYSED PRODUCTS

Fig. 3. The components of the fibrinolytic sy-

stem and their relations. See Chapter 5 for further explanation.

number of other bacteria (staphylococci, coli bacilli, pseudobacilli and others) are known to be fibrinolytically active as well, but to a much lesser degree than the streptococci (Article III). However, it applies to most of these bacteria that their activity is based on plasminogen (Fig.3) or on a production of unspecific proteinases. Furthermore, a number of tissues in human beings as well as in other mammals are believed to contain lysokinases, which may act as proactivator activators. However, they are of little importance compared with the tissue activatorsn, 20,0a,9o. Moreover, blood contains a kinase ("surface factor") which may transform proactivator and is dependent on the Hageman factor 8~. Similar kinases have been found in several secretions, e.g. saliva7 (Article II). I n addition to the activator formed by action on proactivator, a number of agents are known which are capable of transforming plasminogen directly to plasmin. They are activators in blood~2, ~0 and tissues~ (Article IV). The tissue activators are found in two different types: One is easily extracted by saline and is labile, i.e. it loses its activity when heated at a low pH. The other type is

a sparingly soluble, protein-bound activator which is stable and keeps its activity w h e n heated at a low pH. The labile activator m a y originate from the blood, and if so, it is not a real tissue activator ls~. The fibrinolytic activity in tissues seems to be linked up with the microsome fraction, and is released by damage to cells as seen in inflammation and necrosis20, 56, 00 ,~60,la,. Furthermore, plasrninogen activators are found in a number of secretions, such as urine (urokinase) and salivar, ~ (Article II). P1asminogen m a y be activated by a number of proteolytic enzymes, tooT, s~. As mentioned previously, plasminogen may also be activated by various agents such as chloroform, ether and alcohol and by the action of such substances as adrenalha~0. Finally it should be mentioned that fibrinolytic activity may also arise spontaneously in the blood, e.g. in stress and shock in connection with surgical trauma is. Fig. 3 shows, too, that there are a number of inhibitors of the fibrinolytic system. T h e y may act on different phases i'n the activation process and are native, e.g. in blood (antiplasmin)Sa. One of the tissue inhibitors originating from ox lungs should be mentioned 19,28 This inhibitor (Trasylol| has been proved to be a strong inhibitor of the plasmin activityll, x~r. Together with epsilon-aminocaproie acid (EACA), a synthetic inhibitor of the fibrinolytic activityl~7, Trasylol| m a y be used to characterize the active component in the fibrinolysis, as E A C A almost exclusively acts on activators and kinases in the fibrinolytic system~, s. POSSIBLE CAUSES O F THE FIBRINOLYSIS IN FIBRINOLYTIC ALVEOLITIS From the above it appears that the theory of increased fibrinolytic activity as the cause of F A apparently includes several possibilities of the genesis of this activity.

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS T h e fibrinolytie activity may be general or local. The general activity might occur because of the stress and trauma which the patient is exposed to in connection with the extraction6~. The local fibrinolytic activity might have several sources: contamination of the extraction wound with saliva, fibrinolytically active bacteria or tissue fibrinolysis released by inflammation and consequent generation of stable tissue activators which remain local and have no influence on the general fibrinolytic activity of the organism 20. As mentioned previously, several authors have stated saliva to be the source of the fibrinolytie activity 142,145-14s,~00. Investigations by Albrechtsen&Thaysen7 have shown that saliva contains proactivator and small amounts of activator, but no plasmin. Bacteria as the cause of the fibrinolytic activity has also been mentioned beforegB, 156. Especially the [3-hemolytic streptococci with their production of streptokinase have been emphasized. This hypothesis is strengthened by the findings of Brown et al.a9 that the amount of bacteria in the wound as well as in the saliva is significantly higher in patients who develop FA. This, too, applied to the ~3-hemolytic streptococci. On the other hand, BrightmanSS has found only very weak fibrinolytic activity of fS-hemolytic streptococci isolated from the oral cavity. He concluded that these bacteria can hardly be any essential etiologic factor in FA. This, related to the fact that patients who are exposed to infections by fl-hemolytic streptococci develop immunity against streptokinasel0S, makes it not possible that [3-hemolytic streptococci are of any importance in the development of

237

FA. On the other hand, it cannot be excluded that other bacteria which are known to be fibrinolytically active may play an etiologic role in FA. Of the tissues of the oral cavity the mucosa and the epithelial cells are known to be fibrinolytically activeS~,34, r0. These tissues contain activators. Besides, Tsuchia 107 has found activators in the sublingual gland and plasmin activity in the mucosa and the above-mentioned gland. This seems surprising and is not in agreement with the results of other authors. No investigations have been carried out on the fibrinolytie activity of the jawbone. Red bone marrow is known to contain labile activators, whereas yellow bone marrow is almost inactive ss. However, the jawbones contain a type of bone marrow consisting of loose connective tissue rich in cells and with many vessels. Only in young individuals is red bone marrow found; in older inviduals it is fat marrow~S3. Furthermore, it should be mentioned that the periosteum in homo is shown to be strongly fibrinolytic136. Furthermore, Magnusson & Gustafssonl00 have found that the endosteum in rat jaws contains tissue activators. Finally, Goldstein, Wtinschmann, Astrup & I-Ienderson00 have shown that human leukocytes became fibrinolytically active by the action of endotoxins. These cells occur abundantly in the osteomyelitis which is characteristic of F A (see p. 222). Thus, there seems to be a good part of the tissues surrounding the alveolus which may be responsible for a possible fibrinolysis in connection with FA. But nothing is known about the most important tissue, i.e. the alveolar bone.

238

BIRN

CHAFFER 6

Fibrinolytic alveolitis and fibrinolysis In the investigation referred to in Article II the fibrinolytic activity in the alveolus in F A was tested. F r o m 20 patients suffering from FA, test material from the alveolus was taken every second day, from the time the diagnosis of F A was made until the cessation of the disease. Similar test material was taken from 19 patients serving as controls who did not show any signs of complications after tooth extraction or operative removal of the teeth. This test material was obtained until the fourteenth day postoperatively, at which time epithelialization of the wound could be expected (see p. 221). Besides, from both groups of patients test material from the saliva was obtained for testing for fibrinolytic activity. By the fibrin plate method the fibrinolytic activity in the liquid of the alveolus as well as saliva was tested (Article II). This method uses fibrin plates made of bovine fibrinogen. On these plates drops of the active component are placed in concentrations of 100, 50 and 25 % obtained by serial dilution. After incubation at 37~ for 20 h the fibrinolytic activity is measured as the product of two perpendicular diameters of the lysed zone around the drops. Some fibrin plates were used untreated and others were heat-treated, by which the content of plasminogen was destroyed 04. This means that it was possible to distinguish between activator activity and plasmin activity (Fig. 3). Furthermore, E A C A and Trasylol| were added to the plates or the test material, which also made it possible to distinguish between proactivator and activator activity

on one hand and plasmin activity on the other. T h e investigation showed that the fibrinolytic activity in F A is high and strongly connected to the course of the disease as it increases steeply in the first days to reach its maximum shortly before the cessation of the disease and then decreases to the starting value upon cessation of F A (Fig. 4). Furthermore, it was shown that the intensity of the fibrinolysis is proportional to the intensity of F A as expressed by the extent and intensity of the pain and the clinical course (formation of sequester). The activity is probably caused by plasmin, but the methods used cannot exclude any other proteolytic activity. The fibrinolytic activity in F A is much higher than in normally healing alveoli, where only extremely sparse fibrinolysis can be demonstrated (Fig. 5). The difference in fibrinolytic activity is statistically significant (Article II). Finally it was shown that the fibrinolytie activity is increased in all postoperative complications, but is most pronounced in the development of FA. These results are in good agreement with the investigation by Megguier l~s into the fibrinolytic activity in extraction alveoli. He found plasmin activity in the alveoli 5 d after surgical removal of mandibular third molars. These results afforded grounds for a number of conclusions: The fibrinolytic activity i~1 FA is high enough to explain the disintegration of the blood clot in this disease and follows the course of the disease closely. The intensity of the fibrinolysis is proportio-

E T I O L O G Y AND P A T H O G E N E S I S O F FIBRINOLYTIC ALVEOLITIS F.A.

F.A.

220

220

20O

200

180

180

160

160

140

140

120

120

100 80

239

100 q

Q ,',

~, ,, "q

,

i' '

\ '~ '

80

6O

60

i],

40 .q

20

. . . . . . . . . . . 2

4

6

8

10

. 12

14

DAYS A F T E R EX.

Fig. 4. The mean fibrinolytic activity in the alveolus (unbroken line) and saliva (broken line) in patients with fibrinolytic alveolitis (n = 20). F.A. = fibrinolytic activity in mm 2. ~' = onset of fibrinolytlc alveolitis. ~ = cessation of fibrinolytic alveolitis. The fibrinolytic activity in the alveolus increases rather steeply in the first days to reach its maximum 10-12 d after extraction. Then it rapidly decreases to the starting value by the time of cessation of fibrinolytic alveolitis. The activity of saliva varies from one day to another, but shows only a slight increase corresponding to the time of the highest activity in the alveolus.

nal to the intensity of the postoperative complication. Thus, fibrinolysis is found in all postoperative complications as well as in normal healing. But only in F A does it reach such a height that a disintegration of the blood clot takes place. Whether this will be

0

o-..o'" o," [

2

o "d"

"q"

-'~ "'ct"

. . . . . . . . . .

4

6

8

,

10

12

14

DAYS APIt:H EX.

Fig. 5. Mean fibrinolytic activity in the alveolus in fibrinolytic alveolitis (t, nbroken line) 07---" 20) and in the alveolus in normally healing extraction wounds (broken line) (n = 19). F.A. = fibrinolytic activity in mmL "1" = onset of fibrinolytie alveolitis. ~, = cessation of fibrinolytic alveolitis. Analysis of variance gave a significant F-value (P <~ 0.001).

partial or complete depends on the fibrinolytic activity in the alveolus and the c o n tent of antiplasmin in the clot. A f t e r it was shown in this way that in the alveolus in F A there is a fibrinolytic activity of such an extent that one of the most important symptoms in this disease (disintegration of the blood clot) can be explained, the next problem was to find the cause of this fibrinolysis so as to explain the etiology of the disease.

240

BIRN

CHAPTER 7

Etiology of fibrinolysis in fibrinolytic alveolitis GENERAL FIBRINOLYSIS The high fibrinolytic activity in F A (Article II) m a y hardly be of a general character. Such a high, general fibrinolytic activity would no doubt give rise to serious disturbances in the general blood coagulation (hemorrhages), which are never seen in patients suffering from FA, nor in the alveolus itself, which or~ the contrary lacks blood. Finally it should be mentioned that Bjtirlin & Ntisson3a could show no increase in fibrinolytic activity in the circulating blood after oral surgical interventions, even though a local activity in the alveolus was found. Besides, they found in the same patient rather great differences in the activity levels of different alveoli. This, too, indicates that the fibrinolyric activity of the alveolus is of local origin. Finally, the activity was constant and not influenced by the stress and trauma to which the patient had been exposed. Megquier118 reached the same result. On the other hand, Gabler et ai.83 found that the general fibrinolytic activity is increased after oral surgical interventions, especially in patients under psychic stress (lysis time 82 h against 122 h for the control group). But in all circumstances the lysis time for the clot is so long that formation of granulation tissue should have started at this moment (see p. 221). The authors do not believe that general fibrinolysis alone can be responsible for the development of FA. The explanation of the different results in the two above-mentioned investigations may be sought in the

different registration methods used. Bj~Srlin & Nilsson~4 used the fibrin p/ate method, whereas Gabler et al.~S registered the lysis time on undiluted plasma clots. This may explain the long lysis time. Thus, general fibrinolytic activity as an essential cause of F A seems unlikely.

FIBRINOLYSIS IN S A L I V A In Article II it was shown that the fibrinolyric activity in saliva was only slightly increased in F A (Fig. 6) and was much lower than the fibrinolytic activity in the alveolus (Fig. 4). The values for the fibrinolytic activity in the saliva are in good agreement with the results of Albrechtsen & ThaysenV and TiSrteli le6. On the other hand, Schulte & Gewalt 14e and Schulte&Sorg 148 found much higher values for the fibrinolytic activity in saliva. However, the latter authors used fibrin plates made in another way. This may explain the diverging results. Investigation II showed also that in addition to proactivator, saliva contains plasrnin. In contrast to this Albrechtsen & ThaysenV and Schulte & Gewalt ~4~ have found that saliva contains proactivator and small amounts of activator, but no plasmin. The different results may be due to a difference in the methods used. But another explanation is possible, too. A prerequisite of plasmin in the saliva is that plasminogen is or has been present. In the investigation referred to (Article II) plasminogen could originate from the clot in the

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS EA.

241

BACTERIAL FIBRINOLYSIS

120 IO0 80 6O 40

'6

o

2O

2

4

6

8

10

12

14

DAYS AFTER EX,

Fig. 6. Mean fibrinolytic activity in saliva from patients with fibrinolytic alveolitis (unbroken line) (n = 20) and from patients with normally healing extraction wounds (broken line) (n = 19). F.A.=fibrinolytic activity in mme, 1" = onset of fibrinolytic alveolitis. -l, = cessation of fibrinolytic alveolitis. Only minor differences are seen between the courses of the two curves. The activity of saliva in patients with fibrinolytic alveolitis is a little higher than in the control patients, corresponding to 10-12 days after extraction. This corresponds to the time of maximum activity in the alveolus of patients with fibrinolytic alveolitis (see also Fig. 4).

I n Article III an investigation was carried out on the fibrinolytie activity of bacteria isolated from the alveolus in 10 patients with FA. This was done after it had been shown that these patients had a high fibrinolytic activity in the alveolus. The bacteria were grown aerobically as well as anaerobically in both liquid and solid medium. By the fibrin plate method it was not possible to show any fibrinolytic activity of the bacteria, even if human plasma was added to disclose a possible lysokinase activity. As the fibrin-

log F.A. 250 200 140 100 80

.t" r

60

extraction wound. This possibility was not at h a n d in the other investigations. The low fibrinolytic activity in the saliva, which was independent of the existence of F A , gave the grounds for the conclusion that t h e fibrinolytic activity of saliva is not the cause of the activity in the alveolus. The slight increase in the activity of saliva is rather an expression of a leakage of fibrinolyticall~ active material from the alveolus to the saliva. On the other hand, it could n o t be excluded that the fibrinolytic activity i n the alveolus in F A could be caused by bacteria from the saliva, as fibrinolytically active bacteria originating from saliva might grow and concentrate in the optimal environment which the blood clot of the alveolus is to many bacteria. Thus, the fibrinolytic activity in the saliva p e r se can be excluded as the cause of FA.

.0," s

40

20

f.~

s

10 '

lo

~

''

~

'

~o

log CONG. IN .~.

Fig. 7. Mean fibrinolytie activity in centrifuged and washed material from the alveolus in fibrinolytic alveolitis (n = 10). Unbroken line = supernatant. Dot-and-dash line=sediment. Broken line = washed sediment. F.A. = fibrinolytie activity in mm2. The values of the abscissa are obtained by serial dilution. All values are plotted logarithmically. The activities of the sediment and the washed sediment are considerably lower than that of the supernatant. The activity of the washed sediment constitutes about 15 0/o of that of the supernatant.

242

BIRN

log

in connection with F A are not responsible for the fibrinolytic activity and that this activity probably originates from the alveolar bone.

F.A. 250 200 140

T I S S U E FIBRINOLYSIS OF T H E J A W B O N E

100 80

Because, as previously mentioned (see p. 237), it was u n k n o w n whether the jaw bone in homo contains fibrinolytic enzymes, an investigation into this problem was carried out (Article IV). With a trephine, bone biopsies from the alveolar processes were taken in 27

60 i

40

20

log

~0

lO

25

so

1oo log

CONC.IN Z

Fig. 8. Mean fibrinolytic activity of the potassium thiocyanate extracts (unbroken line) and saIine extracts (broken line) from 27 bone biopsies of normal alveolar bone. F.A. = fibrinolytic activity in mm ~. The values of the abscissa are obtained by serial dilution. All values are plotted logarithmically.

F.A. 250 200140100. 60

40'~ olytic activity might be linked up with endotoxins, the bacteria were destroyed by ultrasound. Even in this way no fibrinolytic activity could be proved. It was not possible to isolate [3-hemolytic streptococci, but as previously mentioned their fibrinolytic activity is doubtful3a. On the other hand, it was demonstrated that centrifugation of liquid obtained from the alveolus showed a high activity of the supernatant, whereas the activity of the sediment where the bacteria were found was lower and decreased further by washing of the sediment (Fig. 7). Furthermore it was demonstrated that bone fragments from the alveolus in F A showed a high fibrinolytic activity even if the surface layer of detritus and bacteria was thoroughly irrigated a n d brushed off. On the basis of these findings it was concluded that bacteria

y

20

10

i"

/~/

/

,..,/'""

-

,,, ,,, T"

25

50

100 log CONe.IN Z

Fig. 9. Mean fibrinolytic activity of 10 potassium thiocyanate extracts (plotted by circles) and I0 saline extracts (plotted by squares) from normal alveolar bone. Part of extracts were heated to 37~ at neutral pH (unbroken lines) and part were heated to 37~ at pH = 3 (broken lines). F.A. = fibrinolytic activity in mm ~. The values of the abscissa are obtained by serial dilution. All values are plotted logarithmically. The postassium thiocyanate extracts are unaffected by both treatments mentioned, whereas the activity of the saline extracts decreases when heated at pI-I ~ 3.

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS patients without any sign of inflammation in the biopsy area. In 20 patients the biopsies were taken from the mandibular third molar area and in seven patients from the incisor area. The biopsies were ground and possible tissue activators extracted by saline and potassium thiocyanate (KSCN) to test the content of labile as well as stable activators on fibrin plates (Article IV). Large amounts of tissue activators were demonstrated in both extracts from the alveolar bone (Fig. 8). By heating the two types of tissue extracts to 37~ and changing the p H to 3 in 30 min and subsequently comparing the test material treated in this way with corresponding material without change in pH, it was demonstrated that the K S C N extract contained stable tissue activators and the saline extract almost exclusively labile activators (Fig. 9). Furthermore, it was shown that the content of stable tissue activators was the same in different areas of the jaws. The large content of stable tissue activators in the jawbone is in contrast to investigations by Roberts & Astrup iS6, who found no activator activity in bone from monkeys. Bjtirkman & Nilsson 3s have found that human red bone marrow contains labile, but no stable tissue activators and that fat marrow contains no activators at all. However, a comparison with the results by Roberts & Astrupt3a is hardly permissible as the fibrinolytic activity in different tissues varies considerably from one species to another 5. The investigation by Bj~irkman & Nilsson38 concentrated on types of bone marrow which never, or only occasionally, occurred in the present material (Article IV), which mainly contained loose connective tissue rich in cells and vessels. Thus, it is reasonable to believe that the type of bone marrow is decisive for the content of activators. This is partly substantiated by the fact that the content of labile activator varied quite a lot from one biopsy to another in agreement with their varying content of red bone marrow.

243

In Investigation VII an attempt was made to localize the fibrinolytic activity in the jawbone by the so-called fibrin slide technique developed by ToddJ05. In this method frozen sections are placed on slides coated with a fibrin film, or the sections are covered with a thin fibrin film after having been placed on the slides. After rather short incubation times (5 to 30 min) the sections are fixed and stained. Possible fibrinolytic activity will appear as clear zones in the stained fibrin surrounding the active structures. In Investigation VII biopsies were taken from normal alveolar bone of seven patients. The bone marrow was of the above-mentioned type, rich in cells and vessels. It showed fibrinolytic activity to such an extent that the normal incubation temperature (37~ gave totally distributed fihrinolysis even after the shortest incubation times (5 rain). To make possible a precise localization of the fibrinolytic activity which was due to activator activity, it was necessary to lower the temperature to 25-30~ Because of the condition of the tissue (undemineralized hard tissue) and the heavy fibrinolytie activity, localization of the fibrinolytic activity was difficult, but it looks as if the fibrinolytic activity of the bone marrow has two sources: partly the endosteal layer, probably the osteoblasts, and partly the bone marrow itself, maybe the many vessels (Fig. 10). Thus, Investigation VII confirms that normal alveolar bone has a high fibrinolytie activity caused by activators of plasminogen (Article VII). As previously mentioned the jawbone contains both stable and labile tissue activators (Article IV). q-he present investigation (VII) gives a possible explanation of the origin of these activators. The labile activator could possibly originate from the many vessels in the bone marrow, the endothelial cells of which are known to contain labile activatorslr~. Then the stable activator might originate from the osteoblasts. Especi-

244

BIRN

Fig. 10. A, biopsy of h u m a n alveolar bone. The slide is incubated with a fibrin film for 15 min at about 30~ Weak zones of lysis are seen along the surfaces of the bone trabeculae. X 40. B, same biopsy as in (A) incubated for 40 rnin at about 30~ Pronounced lysis of the fibrin film is seen along the bone trabeculae. )< 40. C, an isolated piece of the loose connective tissue rich in cells and vessels, which fills up the marrow spaces of the alveolar bone. The slide is incubated for 20 rain at about 30~ A circular, lysed zone is seen around the connective tissue. X 400. D, human alveolar bone incubated with a fibrin film for 20 rain at about 30~ A band-shaped lysed zone isseen along the bone trabeculae. There is no bone marrow in the section, but in some areas osteoblasts are seen along the trabecnlae. X 400.

ally in the a l v e o l a r b o n e t h e osteoblastic and osteoclast~c activity is robust because of the c o n t i n u o u s m o v e m e n t of the teeth. T h e r e fore, these cells are n u m e r o u s . T h u s , Investigatiol~ I V has showrt that t h e b o n e s u r r o u n d i n g the alveolus contains, a m o n g o t h e r things, stable tissue activators

which by release m a y explain the local fibrinolytic activity in F A . F r o m Investigation VII is seen the possibility t h a t the stable activator is linked up with the osteoblasts of the endosteum. This is in a g r e e m e n t with the finding by Magnusson & Gustafsson 106 of a high fibrinolytic activity in the endo-

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS log F.A. 25O

2O0 140 100 80

60 40

2O

10 10

25

50

100 Io9 CON(:. INT.

Fig. 11..Mean fibrinolytic activity of potassium thiocyanate extracts on heated fibrin plates (heavy, unbroken line) and on unheated fibrin plates (unbroken line). The extracts are obtained from biopsies of alveolar bone in fibrinolytic alveolitis (n = 10). F.A. = fibrinolytic activity in mmL The values of the abscissa are obtained by serial dilution. All values are plotted logarithmically.

steal layer in rats. Thus, what is left is to prove that such release of tissue activators actually takes place in FA.

TISSUE FIBRINOLYSIS IN F I B R I N O L Y T I C ALVEOLITIS Article V deals with the Iibrinolytic activity in bone biopsies from the alveolus in FA. The investigation was carried out by the same method used in Article IV. From 10 patients suffering from FA and with a high fibrinolytic activity in the alveolus, biopsies of the alveolar walls were taken. The fibrinolytic activity in the alveolus was of the same magnitude as found previously (Article

245

II) (Fig. 4). It was demonstrated that K S C N extract contained tissue activators in large amounts (Fig. 1 l). By acid and heat stability tests (see p. 243) it was confirmed that the activators in question were stable. On the other hand, the content of tissue activators was very poor in the saline extract, which normally contains the labile activators. By using heated fibrin plates, where a urokinase test had shown that all plasminogen was destroyed, small amounts of plasmin were also demonstrated in the KSCN extract (Fig. 1 1). The content of stable tissue activators was of the same magnitude as in normal alveolar bone (Article IV) (Fig. 8). Thus these investigations showed that the alveolar bone in FA contains stable tissue activators and plasmin, but only few or no labile activators. As previously mentioned the labile tissue activator will disappear from the site of liberation when released. It probably diffuses into the bloodstream where it will be inactivated unless it occurs in large amounts 4. On the other hand, the stable activator will remain local because of its protein bond and cause local fibrinolytic activity20. When a comparison [s drawn between the content of the components of the fibrinolytic system in the normal alveolar bone and the alveolar bone in FA, it is seen that such a release probably has taken place (Fig. 12). In contrast to normal alveolar bone, the alveolar bone in F A contains no labile activator. This indicates that the labile activators have been released and have disappeared. The stable activators have remained local, but liberated, too. This is seen from the existence of plasmin in the alveolar bone in FA. The plasmin has been formed by the action of stable tissue activators on plasminogen, which is present in the clot and the thrombi in the marrow spaces. However, the plasmin will hardly be found in areas with living tissue and vessels, as it is rapidly inactivated in these areas. Plasmin will be detected only in necrotic areas and in the alveolus itself,

Z46

BIRN

log EA.

ALVEOLAR BONE IN FA

NORMAL ALVEOLAR BONE

log FoA,

250

250

2O0

200

140

140

100

100 80

8O ,,f

60

6O

40

40 ..t / I

20

20

I

j9

/

/

10 10

i

L

25

50

log CONC. IN .~.

100

25

10

50

10 100

log CONC. IN Y.

Fig. 12. A comparison of mean fibrinolytir activity in normal alveolar bone (n = 20) and alveolar bone in fibrinolytie al'~eolitis (n = 10). Heavy unbroken line = plasmin activity. Unbroken line = stable tissue activator activity. Broken line = labile tissue activator activity. F.A. = fibrinolytie activity in mm ~. The values of the abscissa are obtained by serial dilution. All values are plotted logarithmically. It is seen that normal alveolar bone contains both stable and labile tissue activators, but no plasmin. On the other hand, the alveolar bone in fibrinolytic alveolitis contains only the stable tissue activators, but plasmin is also present.

which are beyond the range of the inhibitors of the living tissues. Some of these areas were incorporated i n the biopsies. The work of Megquier l~s seems to confirm that the tissue activators are released. Just after the extraction he found activators only in the alveolar blood. But after 5 days he found plasmin as well. Thus, Investigation V seems to show that a release of the tissue activators actually takes place i n FA.

CONCLUSION I n this way, one of the most characteristic features in F A , dissolution of the blood clot, seems to be explained by a liberation of tissue activators in the alveolar bone and subsequent dissolution of the blood clot by the action of plasmin. This plasmin is formed by activation of plasminogen in the clot. But it cannot be excluded that tissue activators f r o m the surrounding gingiva and epi-

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS thelium are contributing to this process. However, the activity of epithelial cells is poor3t, just as the amount of gingival tissue is small compared with the alveolar bone. Therefore it seems reasonable to believe that the major part of the fibrinolytic activity comes from the alveolar bone. Maybe in

247

some cases this activity is supported by a slightly increased general fibrinolytie activity63. Likewise, it has been shown that bacteria in themselves, and saliva, play only a minor or no part at all in causing fibrinolytic activity in F A .

248

BIRN

CHAPTER 8

Fibrinolytic alveolitis and kinins G ENERAL ASPECTS Recently a detailed survey of our knowledge of kinins has been given in Handbook o/ experimental pharmacology, vol. XXV 57. Tlaerefore o n l y the aspects relevant to F A will be mentioned in this chapter. Kinins are biologically active polypeptides characterized b y the following properties: (1) they cause contraction of smooth muscles, (2) they cause vasodilation, (3) they increase the capillary permeability, and (4) they are strongly pain producing. Kinins are among the strongest pain producing peptides when c o m p a r e d to, for example, vasopressin and angiotensin. They are also m o r e strongly pain producing than some amines such as histamine 10. Kinins in concentrations as low as 1 ng p e r ml are able to produce intense painaa. The provoked pain is characterized as burning, smarting or pricking16,1r. If the kinins are introduced into deep regions, t h e p a i n often is irradiating 40, 1ol. P r e s u m a b l y the kinins act by stimulating chemoreceptors which terminate as unmyelinated nerve branches around the vessels100. Three types of kinins are known: kallidin I and II and bradykinin. Their biological action is the same, although minor quantitative differences exist. But their chemical structures are somewhat different. Kinins are not n o r m a l l y found in the organism, as t h e y are rapidly inactivated by kininases. O n l y if the well-balanced equilibrium is disturbed, as for example in inflammation, can kinin f o r m a t i o n be demonstra-

ted as the kinin forming enzymes are activated0s, t74. 'F~/en. under these circumstances the kinins are rapidly destroyed under the influence of kininases, and therefore a continuous formation is necessary for their action. In principle all kinins are formed as shown in Fig. 1 3. Prekininogenases are transformed into kininogenases by the action of, among other things, the Hageman factor or piasmin ~-%07, :~D. Kininogenases act on kininogens by splitting off a terminal amino acid, and in this way kinin is formed. A s shown in Fig. 13 plasmin m a y also act as a proteolytic enzyme which decomposes kininogen to kininSt. Prekininogenases and kininogenases are widespread in the organism~S, TS,00,1rs, 17U,17S)I79. Especially pancreas and b o n e marrow contain a high concentration of these agents 173,177. Thus, the high concentration of activators of kininogen in bone marrow c o m p a r e d to the existence in F A of ptasmin, which also m a y act as an activator, may give a possible explanation of the heavy neuralgic and irradiating pain in F A . It may be a result of the action of kinins. As mentioned previously (Chapter 2), it has not yet been possible to explain the occurrence of this pain in a satisfactory way.

KININS IN FIBRINOLYTIC ALVEOLITIS In Investigation V[ the content of kirdrts in alveoli in patients suffering from F A was studied. I t was stated that all patients had a

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS PREKININOGENASE

p

KININOGENASE

KININOGEN

== KININ

Fig. 13. The main components of the kinin forming system and the function of plasmin as an activator. See Chapter 8 for further explanation.

high fibrinolytic activity in connection with the disease. From 15 patients suffering from FA, test material was taken from the alveoli and transferred to test tubes coated with silicon. The tubes were stored at - 6 0 ~ to avoid destroying any kinins. The presence of kinins was shown by the characteristic contraction which they caused on an isolated rat womb placed in a saline bath. As the content of kinins in the strongly diluted material from the alveoli was so low that it Was impossible to calculate the concentration immediately, synthetic bradykinin was added to permit such a calculation. Further-

249

more, the action of known concentrations of synthetic bradykinin was used as a basis for the calculation of the content of kinins in the material from the alveoli (Article VI). Kinins could be demonstrated with certainty in nine out of 15 patients. By the previously mentioned comparison with a standard solution of synthetic bradykinin, the concentration of kinins in the test material could be calculated to be from 0.4 to 54.0 ~tg per ml test material (Fig. 14). This concentration is beyond the threshold value for pain production ((3.1 p.g). I n three cases no kinins could be detected, and in three other cases kinins could be detected but their concentration could not be calculated because of impurities in the test material which influenced the contractile properties of the muscle. Finally the pain producing ability was tested for concentrations found. Cantharidin blisters were produced on the forearm of 10 volunteers. The blisters were opened and synthetic bradykinin was applied to the exposed base in concentrations corresponding to those found in the test material. The vo-

mm

25

2O

1

o..a SEC, x I0

'"'",'"' '"%'I '""" ""%'i'"'"" '""%',"'"'""'" O.2 ml B

0.2 ml B 0.5 ml FA

O.2ml B 1.O ml FA

O.3m~ B

START OF EXPERIMENT

Fig. 14. Typical contraction of an isolated rat womb in 9 cases with a distinct content of kinin in the alveolus. B = synthetic bradykinin. F.A. = diluted liquid from the alveolus in patients with fibrinolytic alveolitis.

250

BIRN

lunteers characterized the pain as moderate to violent and of a pricking and burning character. Often the pain irradiated towards the hand and fingers. Thus, Investigation VI has shown that in the alveolus of patients suffering from FA, kinins are found in concentrations which are pain producing. Three patients out of 15 did not show any kinin activity, but this may be explained by the ease with which kinins are inactivated and the vast content of kininases ha saliva and blood, which migbt have contaminated the test materiaP~, ~: 176.

CONCLUSION Thus there is a basis for supposing that the violent, neuralgic pain in F A is caused by local kinin formation. As previously mentioned, ldnins act on chemoreceptors around the vessels. This is probably the explanation for Chalifour 4t having obtained painlessness by periarterial injection of local anesthetics. The kinin formation may be caused by the content of prekininogenases, kininogenases and plasmin in the alveolus. Furthermore, the presence of the latter enzyme explains the dissolution of the blood clot.

E T I O L O G Y A N D P A T H O G E N E S I S OF F I B R I N O L Y T I C ALVEOLITIS

251

CHAPTER 9

Conclusions concerning etiology and pathogenesis of fibrinolytic alveolitis The previous chapters have referred to a number of investigations which seem to show that F A develops because of high fibrinolytic activity in and around the alveolus. This gives rise to dissolution of the blood clot and the formation of kinins, which in turn causes the violent pain in this disease. In this way the two most important characteristics in F A are explained by a common pathogenesis. The fibrinolytic activity arises from the alveolar bone around the wound by release of stable tissue activators. It is well known that tissue activators are liberated by inflammation in the tissue ~0,1~t, 1~8. But heavy inflammation of the marrow spaces is just characteristic of FA. The inflammation m a y have two different causes: infection of the alveolus or trauma. As previously mentioned (Chapter 3) these are just the two most probable causes of F A . When fibrinolysis is the provoking factor in FA, infection as well as trauma may be the etiology of disease. Thus, the many conflicting opinions as to the importance of the two factors in the release of F A may be due to the fact that one has been more pronounced than the other in the individual cases. Infection and trauma may often work together to create the degree of inflammation which is necessary for the development of FA. Now, the etiology and pathogenesis of F A may be explained as shown in Fig. 15. Infection of the extraction wound during or immediately after the extraction and trauma

cause inflammation of the marrow spaces of the alveolar bone. This gives rise to liberation of tissue activators, which convert plasminogen in the blood clot to plasmin. This dissolves the blood clot and at the same time releases kinins from kininogen, which is also present in the clot. The final result will be dissolution of the blood clot and violent pain. In this connection it should be mentioned that Goldstein et al.06 have shown that bacterial endotoxins are able to release fibrinolytic activity from human leukocytes. Thus, in addition to the liberated tissue activators from the normal cells of the marrow spaces there is a possibility of further fibrinolytie activity originating from cells linked up with the inflammation. This explanation of the development of F A is in good harmony with well-known features in this disease and at the same time explains a number of characteristics which so far have not been satisfactorily elucidated. Among other things this applies to the age distribution in FA. The stable tissue activator seems to be present particularly in the connective tissue type of bone marrow, rich in cells and vessels (Articles IV and VII). As this type of bone marrow is particularly characteristic of the age group with the highest frequency of F A (20-40 years), an explanation of the age distribution is possible. Before the age of 18, when F A seldom or never occurs, the bone marrow is of the hemapoietic type, and after the age of 40 it changes to fat marrow. None of these types

252

BIRN

AS~

TRAUMA AND/OR

~

INFECTION

9 I -c,~,.':~.

INFLAMMATION OF BONE MARROW

Lu llll ill

Ill

I

is transformed to

OF FIBRIN I

I

FORMATION OF KININS

DISSOLUTION OF BLOOD CLOT PAIN

Fig. I5. Illustrated presentation of etiology and pathogenesis of fibrinolytic alveolitis. See Chapter 9 for further explanation.

o f bone m a r r o w contain stable activators which p r o b a b l y are responsible for the local fibrinolytic activity. M a c G r e g o r 102 has shown that F A occurs m o s t frequently in women, Apart from the e x p l a n a t i o n which was suggested on p. 218, a n o t h e r reason might be the increased fib r i n o l y t i e activity in blood and saliva in w o m e n in the menstrual phase ~4r. This increased activity may add to the dissolution o f the b l o o d clot. Teeth extracted in that p e r i o d will therefore show a greater tende n c y towards the development of FA. A s the fibrinolytic activity is the same in d i f f e r e n t areas of the jaws (Article IV), the e x p l a n a t i o n of the preferred location in the m a n d i b u l a r m o l a r area may be that trauma a n d / o r the risk of infection are greatest in

this area. This seems to be substantiated by the heavy alveolar bone in the mandibular molar area connected with the great risk of admission of saliva into these alveoli. The time of onset of F A m a y vary, but most often takes place on the second day postoperatively. The explanation of this is to be sought in the fact that the blood clot contains antiplasmin, which must be used up before dissolution of the clot takes place. At the same time the deg,'ee of inflammation will be decisive for the degree of fibrinolyric activity and thus for the time for inactivation of the antiplasmin. Thus fibrinolytic activity as the provoking factor in the development of F A seems to give a satisfactory explanation of the etiology as well as the pathogenesis of this dis-

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS ease. Therefore the expression "fibrinolytic alveolitis" is suggested as the name of the disease. It is not because of a special pathophysiologic picture in this disease that a special expression for the disease in recommended. As mentioned in Chapter 6, increased fibrinolytic activity is seen in all complications to tooth extraction. The only characteristic in F A is that the fibrinolytic

253

activity reaches such levels that dissolution of the blood clot takes place. However, the clinical picture is characteristic, and the course and nature of the disease are of such character that a special treatment of the complication is necessary. These circumstances justify giving the disease a special designation.

254

BIRN

CHAPTER 10

Final remarks T h e explanation of the etiology and pathogenesis of F A as put f o r w a r d in the present work will be o f importance in the prevention and treatment of F A . Prevention m a y be directed towards either the fibrinolytic activity itself or the cause of its liberation: inflammation of the alveolar bone. If the inflammation is caused mainly by bacterial infection, c h e m o t h e r a p y will be ideal. As a m a t t e r of fact, the effectiveness of local chemotherapeutics has been substantiated by m a n y investigations (Chapter 3). The ease is more difficult if the inflammation is caused by trauma. Antiphlogistics might be effective, but chemotherapy is useless. This possibly explains why a complete reduction of the number of F A is never seen when c h e m o t h e r a p y is applied. On the other hand, the fibrinolysis itself may be p r e v e n t e d by the administration of an antifibrinolytic drug, as for example E A C A . F r o m a theoretical point of view this drug should be suitable, as it especially acts on the tissue activators, which are the provoking factor in the fibrinolysis. But such drugs as Trasylol| seem to b e less suitable for purposes of prophylaxis as they act on plasmin only a n d thus do not become active until the tissue activators have already been liberated. F r o m a theoretical point of view both E A C A and such drugs as Trasylol| may be used in the treatment of FA, as the problem here is to inactivate plasmin already formed and prevent the continual formation. Finally a drug, the antifibrinolytie effect of which

has only recently been discovered, should be mentioned. It is propyl-hydroxy-benzoic acid, which acts as an inhibitor of proactivator, activator and plasminX4L In a later investigation Birn 80 has shown that propylhydroxy-benzoic acid, which is a component of Apernyl| - a dental cone, has a pronounced inhibitory action on the fibrinolytic activity in F A . Whether special treatment of the pain in F A is necessary depends on how quickly an antifibrinolytic drug can inhibit plasmin formation. Without plasmin formation the formation of kinin should cease. Should special treatment of the pain be necessary, the ideal treatment would be a direct inhibition of the kinin formation or inactivation of kinin already formed. In this respect acetylsalieylic acid seems to be suitable, as its analgesic effect seems to be attributable to an inhibition of kinin formationlL Whether the above-mentioned drugs have any prophylactic effect is not yet known. But the theory of etiology and pathogenesis of F A which has been put forward suggests that it m a y be possible to find drugs which will have a curative effect on F A . This is in contrast to all drugs used up to now, which have had a symptomatic effect only. These considerations suggest, therefore, on what aspects further investigations should be c o n centrated.

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS

255

Summary The aim of this thesis has been to elucidate the etiology and pathogenesis of fibrinolytic alveolitis (FA) ("dry socket"). Chapter 1 expounds the characteristic clinical appearance and the many designations of the disease. Chapter 2 reviews the clinical appearance and pathogenesis. It is pointed out that a number of characteristics in the disease have not been satisfactorily explained by what has been known about F A up to now. This applies to the age distribution, the dissolution of the blood clot, and the violent, neuralgic pain. Chapter 3 itemizes the suggestions which have been put forward as to the etiology of the disease. The suggested general factors are excluded as being of no importance in the development of FA. Likewise a great number of the many local factors may be excluded, whereas other factors may be grouped with the following four possible causes, which are considered the only probable ones: (1) insufficient blood supply to the alveolus, (2) increased fibrinolytic activity in and around the alveolus, (3) trauma to the alveolar bone during extraction and (4) infection during or after extraction. In Chapter 4 the result of Investigation I is mentioned. This is an investigation of the blood supply to the alveolus and, with that, the possibilities of healing after extraction. It is shown that the blood supply is best to the alveoli of the mandibular molars, where the incidence of FA is the highest. On the basis of this it is concluded that insufficient

blood supply cannot be the cause of FA. In Chapter 5 our knowledge of fibrinolysis and the factors involved are briefly discussed with special reference to their importance in the development of FA. It is concluded that there may be several possible sources of the fibrinolytic activity. The fibrinolysis may be of general or local character, originating from saliva or its bacteria, or caused by a local release of tissue activators. Chapter 6 mentions the results of Investigation II. This investigation showed that the fibrinolytic activity is highly increased in FA and strictly follows the course of the disease. The activity is of such an extent that it may explain the dissolution of the blood clot. The activity is probably caused by plasrain. Furthermore, it is shown that the fibrinolytic activity is increased in other complications to extractions, too, although to a lesser degree. It is concluded that the increased fibrinolytic activity in FA is responsible for the dissolution of the blood clot. Chapter 7 reviews Investigations II, III, IV, V and VII, which dealt with the etiology of the fibrinolysis. Investigation II showed that the fibrinolytic activity in saliva is only slightly increased in FA and concluded that saliva cannot be the cause of the highly increased fibrinolytic activity in FA. Investigation III studied the fibrinolytic activity of bacteria isolated from FA. None of the bacteria found were fibrinolytically active. Furthermore, separating the liquid of the alveolus by centrifugation showed that the super-

256

BIRN

n a t a n t is active, whereas the sediment, where the bacteria are found, has a much lower activity. This activity decreases further by washing of the sediment. Finally it was shown that bone fragments from the alveolar bone in F A are highly fibrinolytically active after thorough washing and cleaning to r e m o v e the main part of detritus and bacteria. On the basis of these observations it is concluded that bacteria are not responsible for the fibrinotytic activity in FA. The source of the activity should rather be sought in tissue activators of the alveolar bone. Investigation IV showed that the alveolar bone contains a large amount of labile as well as stable activators. These may derive from the endothelium of the vessels and the osteoblasts, respectively, in the bone m a r r o w rich in cells and vessels (Article VII). Investigation V studied the content of tissue activators in the alveolar bone from F A and showed that this alveolar bone contains stable tissue activators, but no labile activators. On the other hand, plasmin is found. These observations compared to those mentioned in Investigation IV led to the conclusion that tissue activators are released in F A and are present in such proportions that they may explain the increased fibrinolytic activity in FA.

Chapter 8 briefly mentions kinins and their importance as pain producers. Then the reader is referred to Investigation VI, which dealt with the content of kinins in the alveolus in F A and showed that the alveolus contains kinins in concentrations large enough to explain the severe pain in FA. Kinins m a y be formed by plasmin, and it is concluded that the fibrinolytic activity in F A is responsible for the two most essential characteristics in this disease: dissolution of the blood clot and the violent pain. Chapter 9 elucidates a proposed etiology and pathogenesis of F A rendered probable b y the previously mentioned investigations: trauma and/or infection in the alveolus cause inflammation, which releases the tissue activators. These give rise to plasmin formation, which causes dissolution of the blood clot and severe pain. Finally it is shown that a number of hitherto poorly explained characteristics in F A may be explained by this theory. Chapter 10 mentions the implications which the new theory of the etiology and pathogenesis m a y have for prophylaxis and treatment of F A . At the same time these implications show which ways future investigations within this field should take.

E T I O L O G Y AND PATHOGENESIS O F F I B R I N O L Y T I C ALVEOLITIS

References (Search for literature ceased July Ist, 1971) The numerals in brackets refer to the page numbers in brackets in the thesis where the authors in question are referred to. 1. ABLorqot, F. B. & J. J. HAGAN: Comparison of certain properties of human plasminogen and "proactivator". Proc. Soc. Exp. Biol. (N. Y.) 1957, 95: 195-200. (235). 2. Am.ONDI, F. B., J. J. HAOAN, M. PHIL1PS & E. C. Dr,. RElqZO: Inhibition of plasmin, trypsin and the streptokinase activated fibrinolytic system by e-aminocaproic acid. Arch. Biochem. Biophys. 1959, 82: 153-160. (236). 3. ADKISSON,S. R. & P. F. HARRIS; A statistical study of alveolar osteitis. U. S. Armed Forces Med. J. 1956, 7: 1749-1754. (217, 218, 220, 225, 227, 228). 4. ALERECHTSEN, O. K.: The fibrinolytic agents in saline extracts of human tissues. Seand. d. Clin. Lab. Invest. 1958, 10: 9196. (245). 5. ALBRECHTSEN, O. K.: Fribrinolytic activity in the organism. Acta Physiol. Scand. 1959, 47: suppl. 165. (236, 243). 6. ALBRETCHSEN,O. K., O. STORM t~. M. CLAASSEN: Fibrinolytic activity in some human body fluids. Scand. J. Clin. Lab. Invest. 1958, 10: 310-318. (236). 7. ALBRETCHSEN, O. K. & I. H. THAYSEN:Fibrinolytic activity in human saliva. Acta Physiol. Scand. 1955, 35: 138-145. (236, 237, 240). 8. ALIOAERSlG, N., A. P. FLETCHER& S. SHERI~V: e-aminocaproic acid: an inhibitor of plasminogen activation. 1. Biol. Chem. 1959, 234: 832-837. (236). 9. ALLING, C. C.: Postextraction osteomyelitic syndrome. Dent. Clin. North Am. 1959, p. 621-636. (217, 226). 10. ALLINO, C. C. & ]~. A. K~rta: Trauma as a factor causing delayed repair of dental extraction sites. J. Oral SurE. 1957, 15: 3-11. (217, 221, 227, 228). 11. AMRIS, C. J.: Inhibition of fibrinolytic and thromboplastic activity by Trasylol| Scand. J. HaematoL 1966, 3: 19-32. (236). 12. AMUNDSEN, E. & K. NUSTAD: Kininase activity of human saliva. Nature (Lond.). 1964, 201: 1226-1227. (250). 13. ANDERSSON, L., I. M. Nrr ssoN & B. Ol_ow: Fibrinolytic activity in man during sur-

257

gery. Thromb. Diath. Haemorrh. (Stuttg.). 1962, 7: 391-403. (236). 14. ANtJRADE, C. F. tin: Profilaxia das alveolites. Considerac6es. Ann. Fac. Odont. (Rio de J.). 1965[66, 18/19: 111-114. (223). (223). 15. ARCHER, H. W.: An analysis of 226 cases of alveolalgla. J. Dent. Res. 1939, 18: 256257. (218, 225, 227, 228). 16. ARMSTRONG, D.: Pain. In: ERDSS, E. G. (ed.): Bradykinin, kallidin and kallikrein. Handb. Exp. Pharmacol. Springer Verlag, Berlin 1970, 25: 434-481. (248, 254). 17. ARMSTRONG, D, R. M. L. DRY, C. A. KEELE & J. W. MARKHAM: Observations on chemical exitants of cutaneous pain in man. J. Physiol. (Lond.). 1953, 120: 326-351. (248). 18. ARMSTRONO,J. E.: Challenging dry socket theories. Calcium inbalance advanced as a new theory. Dent. Surv. 1940, 16: 897900. (223, 224). 19. ASTRUP, T.: Ox lung tissue as a proteolyfic inhibitor. Acta Physiol. Scand. 1952, 26: 243-251. (236). 20. ASTRUP, T.: Fibrinolysis in the organism. Blood. 1956, 11: 781-806. (236, 237, 245, 251). 21. ASTRUP, T.: Fibrinolytic mechanisms in man and animals. In: JOHNSON, S. A. & M. M. ernEST (ed.): Dynamics o/ t h r o m b u s ]ormation and dissolution. Lippineott Co. Philadelphia 1969: p. 275-306. (235). 22. ASTRUP, T. & O. K. ALBREeHTSEN:Estimation of the plasminogen activator and the trypsin inhibitor in animal and human tissues. Scand. J. Clin. Lab. lnvesl. I957, 9: 233-243. (236). 23. As'-raur, T. & P. M. P~RMIN: Fibrinolysis in the animal organism. Nature (Lond.). 1947, 159: 681-682. (235). 24. Asaxor, T. & P. M. PERMIr~: Fibrinokinase and fibrinolyfie enzymes. Nature (Lond.). 1948, 161: 689-690. (235). 25. ASTRU~, T. & I. S'I~Rm~O'arF: An activator of plasminogen in normal urine. Proc. Soc, Exp. Biol. (N. Y.). 1952, 81: 675-678. (236). 26. ASTRLrP, T. & I. STERNDORFF:Fibrinolytie activity of tissue extract and of trypsiu. Nature (Lond.). 1952, 170: 981. (236). 27. BELDING, "P. H. r L. J. BELDING: Postextraction infections: preliminary report on the oral flora. J. Am. Dent. Assoc. 1934, 21: 1222-1227. 28. BERALDO, W. T., W. FELDBERO & S. M.

258

29.

30. 31.

32. 33.

34.

35. 36. 37.

38. 39.

40.

41.

42.

BIRN

HILTON: Experiments on the factor in urin forming substance U. J. Physiol. (Lend.). 1956, 133: 558-565. (248). BI~3oS, R.., R. G. MAcFARL~U'~E& J. PILLIne: Observations on fibrinolysis. Experimental production by exercise or adrenaline. Lancet. 1947, I: 402-405. (236). (236). Bml,r, H.: Antifibrinolytic effect of Apernyl| in "dry socket", lnt. I. Oral Surg. 1972, 1: 190-194. (254). Bmrr H. & O. FErERSKOV: Fibrinolytic activity of human oral epithelial cells. A preliminary report. Scand. J. Dent. Res. 1971, 79: 381-386. (237, 247). BJL~cKE, B.: Dry socket. En oversikt. Nor. Tavnlaege/oren. Tid. 1960, 70: 153163. (217, 220, 222, 223). BJgIRK.MAN, S. E. & I. M. NILSSOU: Demonstration of a fibrinolytic activator in red bone marrow. A c t a Haematol. (Basel). 1961, 26: 273-280. (237, 243). BJOaLIN, G. & I. M. NILSSON: Fibrinolyric activity in alveoli after tooth extraction. Odontol. Revy. 1968, 19: 197-204. (237, 240). BOYNE, P. L: Osseous repair of the postextraction alveolus in man. Oral Surg. 1966, 21: 805-813. (221). BRABANT, H. & D. BERKENBAUIv[:La eicatrisation des plaies buccales. Arch. Stomatol. (Liege). 1958, 13: 131-163. (226). BRANZr, A. & G. KOVACS: Lokalanwendung des Aureomycins in der Prophylaxe und Behandlung der Alveolitis. Zahnaerztl. Welt. 1953, 8: 153-156. (226, 228). BamI-ITMAN, V.: The fibrinolytic activity of some oral streptococci. Aust. Dent. J. 1957, 2: 228-230. (237, 242). BROWN, L. R., S. S. M_~RRmL & R. E. .ALLEN: Microbiologic study of intraoral wounds. 1. Oral Surg. 1970, 28: 89-95. (228, 237). Btmc~, G. E. & N. P. DE PAsQuxr.~: Bradykinin, digital blood flow and the arteriovenous anastomoses. Circular. Res. 1962, 10: 105-115. (248). CHALrFOUR,R.-L.: Therapeutique des algies alveolitiques par des injections peri-arterielles de novocaine. Schweiz. Monatsschr. Zahnheilkd. 1969, 79: 1323-1348. (218, 222, 250). C-'rmlsToprmR, R. E.: A histological study of bone healing in relation to the extraction of teeth. North West Univ. Bull. Dent. Res. 1942, 43: 5-11. (220).

43. CMUDZ~SKI, J. G.: A clinical evaluation of aseptic technic on post-operative complications following the removal of impacted mandibular third molars. North West Univ. Bull. Dent. Res. 1954, 5$: 812. (228). 44. CL~Ln% R. S.: Healing of disturbed and undisturbed extraction wounds. J. A m . Dent. Assoc. 1936, 23: 945-959. (220, 221, 228). 45. COMMISSlONAT, Y.: Quelques considerations sur la pathogenic des alveolites. Actual. Odontostomatol. 1964, 18: 203220. (223, 224, 226, 229). 46. CONZ&P. I. DI: Localized alveolar osteitis and terramycin. N. Y. State Dent. J. 1953, 19: 518-522. (225, 228). 47. C'RAWFO•D, J. Y.: Dry socket. Dent. Cosrues., 1896, 38: 929-931. (217, 220). 48. DAY, C. D. M. & K. L. SHolmm: A roentgenographie survey of periodontal disease in India. 1. A m . Dent. Assoc. 1949, 39: 572-588. (232). 49. DOKU, H., G. SHKLAR& B. BUOBEE: The effect of epsilon aminocaproic acid on the healing of extraction wounds in hamsters. Oral Surg. 1966, 22: 569-577. (229). 50. EDITOR: Dry socket: a review. Dent. Abstr. 1967, 12: 479-484. (217). 51. EIS~S, V.: Kinin formation and fibrino]ysis in human plasma. J. Physiol. (Lend.). 1963, 166: 514-529. (248). 52. EIs~.',I, V. & W. VOOT: Plasma kiniltogenases and their activators. In: ERD6S, E. G. (ed.): Bradyklnin, kallidin and kallikrein. Handb. exp. Pharmacol. Springer Verlag, Berlin 1970, 25: 82-130. (248). 53. ELLIOTT, D. F., E. W. HORTON & P. LEWIS: Actions of pure bradykinin. J. Physiol. (Lend.). 1960, 153: 473--480. (248). 54. ELWELL, K. R.: A new approach to the treatment of dry socket. I. A m . Dent. Assoc. 1944, 31: 615-621. (224, 229). 55. EMAN, V. H.: The dry socket problem. J. Oral Surg. 1944, 2: 158-166. (223, 229). 56. EUDE, N. & ]'. AUD1TORE: Fibrinolytie activity of human tissues and dog mast cell tumors. A m . J. Clin. Pathol. 1961, 36: 16--24. (236). 57. ERD6S, E. O. (ed.): Bradykinin, kallidin and kallikrein. Handb. exp. Pharmacol. 25: Springer Verlag, Berlin 1970. (248). 58. ERD6S, E. O. & H. Y. T. YONO: Kininases. In: ERDSS, E. G. (ed.): Bradykinin, kallidin and kallikrein. Handb. exp.

E T I O L O G Y AND P A T H O G E N E S I S OF FIBRINOLYTIC ALVEOLITIS

59.

60.

61.

62. 63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

Pharmacol. Springer Verlag, Berlin 1970, 25: 289-323. (248, 250). ERICKSON, R. T., D. E. WHITE. & R. 1-I. W1LKISON: A study of dry sockets. Oral Surg. 1960, 13: 1046-1050. (223, 227). EULEa, H.: Die Heilung yon Extraktionswunden. Dtsch. Monatsschr. Zahnheilkd. 1923, 41: 685-700. (220, 221). FAILLO, P. S.: Proteolytic enzyme treatment for the necrotic alveolar socket (dry socket). Oral Surg. 1948, 1: 608-613. (217). FEARNLY, G. R.: Fibr#iolysis. Edward Arnold, London, 1965, pp. 16-17. (236). GABLER, W. L., W. 3". TxmmT, L. S. FOSDICK & E. G. FREDERICH: The effect of stress, streptokinase and iodine on the plasmin system as determined by clot lysis. J. Dent. Med. 1964, 19: 3-8. (229, 237, 240, 247). GALLIARD,A.: Qu'est-ce que l'alveolite. Rev. Franc. Odontostomatol. 1966, 13: 581-586. (223). GARDNER, B. S.: Postoperative considerations regarding extraction of teeth. I. Am. Dent. Assoc. 1929, 16: 235-242. (223, 229). GOLDS'rEIN, I. M., B. WONSCHMANN, Z. ASTRLrP & E. S. HENDERSON: Effects of bacterial endotoxin on the fibrinolytic activity of normal human leukocytes. Blood. 1971, 37: 447--453. (237, 251). GO'I-rLIEa B. & H. M. CRAWFORD: Therapy and prophylaxis of dry socket. Oral Surg. 1943, 29: 328-331. (227). GRANDSTAFF, C. H.: The influence of the oral bacteria on the healing of exodontia wounds. Bur 1935, 95: 90-93. (228). GUSTAFSON, G'. & K. WALLENIUS: Effect of local application of trypsin on postextraction alveolar osteitis. Oral Stirs. 1961, 14: 280-286. (218, 224). GUSTAFSON, G. T. & I. M. N~LSSON: Fibrinolytic activity in fluid from gingival crevice. Proc. Soc. Exp. Biol. (N.Y.). 1961, 106: 277-280. (237). HAHN, W. Die Wundheilungssttlrungen der Extractionswunden und die Wege zu ihre Vermeidung. DDZ. 1962, l~i: 431--433. (218, 220, 225, 226, 228). HAHN, W. & D. LANOE: Zahnentfernung und Versorgung der Alveole als erste praeprothetisch-Chirurgische Massnahme. Dtsch. zahnaerztl. Z. 1966, 21: 354-362. (218, 220, 225, 228). HALL, H. D., B. S. BILDMAN r C. D. HAND: Prevention of dry socket with

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

259

local application of tetracycline. J. Oral Surg. 1971, 29: 35-37. (219, 228). HANSm% E. H.: Alveolitis sicca dolorosa (dry socke0: Frequency of occurrence and treatment with trypsin. 1. Oral Surg. 1960, 18: 409-416. (217, 218, 219, 220, 227). HAaANG, H. C.: The prevention of dry sockets in the extraction of teeth. Oral Sllrg. 1948, 1: 601-607. (223, 226). HARNISCI.LH.: Zur Prophylaxe des dolor post extractionem. Zahnaerztl. Welt 1949, 3: 55-59. (226, 228). HAYASHI, S.: Untersuchungen fiber die arterielle blutversorgung des Periodontiums. Dtsch. Monatsschr. Zahnheilkd. 1932, 50: 145-179. (224, 231). HILTOS, S. M. & G. P. L~WlS: The mechanism of the functional hyperaemia in the submandibular salivary gland. 1. Physiol. (Loud.). 1955, 129: 253-271. (248). HtmBscrI, R. F.: Clinical and histological studies of alveolar osteitis. J. Oral Surg. 1958, 16: 473--482. (22I, 224, 226). Htm~SCH, R. F., R. D. COLEMAN, .A. 1V[. FRANDSEN & H. BECrlS: The healing process following molar extraction on male rats (Long-Evans strain). Oral Surg. 1952, 5: 864-876. (220, 221). IAa'RIDIS, S. G. & I. H. FERGtrSON: Active Hageman factor: a plasma lysokinase of the human fibrinolytic system, d. Clin. lnvest. 1962, 41: 1277-1287. (236). JACOBSSON,K.: Studies on the proteolytic and antiproteolytic activity of blood serum I. Activation of plasminogen with trypsin. Acta Chem. Scand. 1953, 7: 430434. (236). JACOBSSON, K.: I. Studies on the determination of fibrinogen in human blood plasma. 11. Studies on the trypsin and plasmin inhibitors in human blood serum. Scand. 1. Clin. Lab. Invest. 1955, 7: suppl. 14, pp. 87-94. (236). JOHANSEN,J. R.: Repair of the postextraction alveolus in the wistar rat. A hlstologic and autoradiographic study. Acta Odontol. Scand. 1970, 28: 1-21. (220, 221). JOHANSEN, J. R. & O. GILHUUs-MoE: Repair of the postextraction alveolus in the guinea pig. A histological and autoradiographic study. Acta. Odontol. Scand. 1969, 27: 249-258. (220, 221). KAT'rERBACH,R. & H. KR66ER: Untersuchungen zur Behandlung des Dolor post Extractionem. DDZ. 1966, 20: 475-479. (222, 225, 226, 228).

260

BIRN

87. KAY, L. W.: Investigations into the nature of pericoronitis. II. Br. J. Oral Surg. 1966, 4: 52-78. (225, 226, 228). 88. KLI~, D. L. & J. B. FlSnMAN: Plasmin: the humoral protease, A N N . N. Y. Acad. Sci. 1957, 68: 25-36. (235). 89. KONTrlNEN, Y.P.: Fibrinolysis. Chemistry, physiology, pathology and clinics. Star pharmaceutical Manufactures. Tampere, Finland 1968. (235). 90. KRALrr, H., E. K. FREY, E, WERLE & F, SCHULTZ; Nachweis und Vorkommen des Kallikreins im Ham. Hoppe-Seylers Z. Physiol. Chem. 1934, 230: 259-277. (248). 91. KROGrr, H. W.: Incidence of dry socket. J. Am. Dent. Assoc. 1937, 24: 1829-1836. (218, 219, 220, 225, 226, 227). 92. KROGH, H. W.: Prevention of dry sockets. J. Dent. Res. 1948, 27: 3-8. (228). 93. LACK, C. H. & S. Y. Am: Tissue activator of plasminogen. Nature (London). 1964, 201: 1030-1031. (236). 94. LASSEN, IV[.: Heat denaturation of plasminogen in the fibrin plate method. Acta Physiol. Scand. 1953, 27: 371-376. (238). 95. LmlNER, T.: Analysis of one hundred cases of dry socket. Dent. Pract. Dent. Rec. 1958, 8: 275-279. (224, 225, 226, 228). 96. LEHN~RT, S.: Zur .Ktiologie, Diagnose und Therapie des Dolor post Extractionem. DDZ. 1966, 2~: 344-354. (217, 221, 222, 228, 229, 237). 97. L~wTs, G. P.: Formation of plasma kinins by plasmin. J. Physiol. (Lond.). 1958, 140: 285-300. (248). 98. LEwxs, G. P.: Pharmacological actions of bradykinin and its role in physiological and pathological reactions. Ann. N. Y. Acad. Sci. 1963, 104: 236-249. (248). 99. L~w~s, J. H. & J. H. FER~usor~: Studies on a proteolytic enzyme system of the blood. II Fibrinolysokinase activators for profibrinolysin. J. Clin. Invest. 1950, 29: 1059-1068. (236). 100. L1M, R. K. S.: Pain mechanisms. Anaesthesiology. 1967, 28: 106-110. (248). 101. LIM, R. K. S., D. G. MILLER, F. GUZMAN, D. G. RODGERS, R. W. ROGERS, S. K. WANG, P. Y. C'HAO & T. Y. SHIn: Pain and analgesia evaluated by the intraperitoneal bradykinin-evoked pain method in man. Clin. Pharmacol. Ther. 1967, 8: 521542. (248). 102. MAcGREGOI~t,A. J.: Aetiology of dry socket: A clinical investigation. Br. J. Oral

103.

104.

105.

106.

107.

108.

109.

110.

112.

113.

114.

115. 116.

117.

Surg. 1968, 6: 49-58. (218, 219, 220, 223, 225, 226, 227, 252). MACGREGOR, A. J.: The bacteriology o/ dry socket: the effect of zink oxide and oil of cloves. In: WALTHER,R. V. (ed.): Trans. 3rd Int. Conf. Oral Surg. Livingstone, London 1970, pp. 424-429. (228). MACGREGOR, A. J. & P. HART: Effect of bacteria and other factors on pain and swelling after removal of ectopic mandibular third molars. J. Oral Surg. 1969, 27: 174-179. (228). MACGREGOR, A. J. & P. HART: Bacteria of the extraction wound. J. Oral Surg. 1970, 28: 885-887. (228). MAGNUSSON, B. & G. T. GUSTAFSSON: Localisation of fibrinolytic activity during tooth eruption in rat. Personal communication, 1972. (237, 244). MANGOS, J. F.: The healing of extraction wounds. N. Z. Dent. I. 1941, 37: 4-23. (220-221). MASSEY, K. M.: Alveolar osteitis: etiology, pathology, treatment and prevention. Q. Natl. Dent. Assoc. 1959, 18: 5-14. (217, 226). MA'ruls, I-I. & H. SCr~XCRTER: ~3ber die Entfernung retinierter Z~.hne. Z. Stomatol. 1937, 35: 1136-1155. (224). Mclrcr~E, H., F. NOtrR-ELmN, M. C. C. ISRAgLS & J. F. WILKINSON: Dental extractions in patients with haemophilia and christmas disease. Lancet. 1959. II. 642646. (227). MclC~vITT, F. H,: Atrophy and hypertrophy of the maxillary and mandibular alveolar process and their effect on the stability of artificial dentures, J, Am. Dent. Assoc. 1932, 19: 424-452. (224). MEGQtrmR, R. M.: Fibrinolytic activity in human dental sockets after extractions. J. Oral Surg. 1971, 29: 321-328. (238, 246). MENZEL, H. J.: Die Behandlung der Ostitis post Extractionem mit Apernyl| D D Z . 1969, 23: 80-83. (217). MEYER, R. A.: Effect of anaesthesia on the incidence of alveolar osteitis. J. Oral Surg. 1971, 29: 724-726. (226). MEYER, W.: Die Heilung yon Ekstraktionswunden unter abnormen Verh~iltnissen. ZI Stomato[. 1924, 22: 521-549. (221, 228). MrLLHOrn~, J. A., L. T. AUSTIN, E. C. STAFrZE & B. S. GARDNER: An evaluation of the sulfa drug and other dressings in "dry socket" in lower third molars. J. Ant.

E T I O L O G Y A N D P A T H O G E N E S I S OF FIBRINOLYTIC ALVEOLITIS

118.

119.

120.

1.21.

122.

123.

124.

125.

126.

127.

128.

129.

130.

Dent. Assoc. 1943, 30: 1839-1844. (219, 224, 228). MmSTONE, J. H.: A factor in normal human blood which participates in streptococcal fibrinolysis. J. lmmunol. 1941, 42: 109-116. (235). MOLT, F. F.: Diet as a factor in healing. J. Am. Dent. Assoc. 1936, 23: 1442-1446. (223). MULLERTZ,S,: A plasminogen activator in spontaneously active human blood. Proc, Soc, Exp, Biol, (N. Y.). 1953, 82: 291-295. (236). IV[ULLERTZ,S. & M. LASSEN; An activator system in blood indispensable for formation of plasmin by streptokinase. Proc. Soc. Exp. Biol. (N. Y.). 1953, 82: 264-268. (235). I'qAW^RA, I.: L'alveolite et son traitement. ln]orm. Dent. (Paris). 1969, 51: 2903-2913. (222, 223, 225, 226). NEUNER, O. & H, K. SCHE~O: Erfahrungen mit Apernyl| bei der Behandlung und Verh(itung des Dolor Post Extractionem. Schwelz. Moaatsschr. Zahnheilkd. 1969, 79: 630-635. (222). NORMAN, P. S.: Studies of the plasmin system. II. Inhibition of plasmin by serum or plasma. J. Exp. Med. 1958, 108: 53-68. (236). NORMAN,P. S. & B. M. HILL: Studies of the plasmin system. III. Physical properties of the two plasmin inhibitors in plasma. J. Exp. Med. 1958, 108: 639-649. (236). OHM, H. l.: Beobachtungen bei der Heilung der Extraktionswunde unterer Weisheitsziihne. Zahnaerztl. Welt. 1969, 78: 456-461. (224). OKAMOTO, S., T. NaKaaMA, U. Or,~MOTO, H. WATANABE, Y. IGUCHI, T. IGAWA, C. CHIEN ~r T. ]-'IAYASHI:A suppressing effect of e-amino-n-caproic acid on the bleeding of dogs, produced with the activation of plasmin in the circulatory blood. Keio Y. Med. 1959, 8: 247-266. (236). OLECH, E.: Value of implantation of certain chemotherapeutic agents in sockets of impacted lower third molars. J. Am. Dent. Assoc. 1953, 46: 154-159. (219). PAINE, W. S.: Post-extraction complications. Aust. Dent. J. 1937, 9: 183-188. (227, 228). PARmTr, J. B.: Symposium on extraction of teeth. IV. Complications and sequelae of extraction. B. Dent. J. 1938, 65: 355366. (223, 225).

261

1.31. PELL, G. J.: So-called dry socket. I .Am. Dent. Assoc. 1934, 21: 1062-1065. (222, 223, 224, 225, 228). 132. PODOLm, N.: The etiology, prediction and treatment of dry socket. Dent. Cosmos. 1936, 78: 1038-i043. (226). 133. PROVENZA,D. V.: Oral histology. Inheritance and development. Lippincott Company, Philadelphia 1964, p. 323. (237). 134. QUINLEY, J. F., R. Q. ROYER & R. J. GORES. "Dry socket" after mandibular odontectomy and use of soluble tetracycline hydrochlorlde. Oral Surg. 1960, 13: 38.-42. (228). 135. RASMUSSEN, J. • O. K. ALBRECHTSEN: Characterization of the fibrinolytic components in the human prostate. Scand. J. Clin. Lab. b~vest. 1960, 12: 261-268. (236). 136. ROBERTS,I"I. R. & T. ASTRUP" Content of tissue activator of plasminogen in monkey tissues. Thrombos. Diathes. haemorrh. (Stuttg.). 1957, 1: 376-379. (237, 243). 137. ROTHm,m~RO, F. & R. LANDMAN: A review of drug therapy for dry socket. J. Oral Ther. Pharmacol. 1965, 2: 229-233. (224). 138. ROVLN, S., E. COSTml-I, J. E. FLEMING & H. A. GORDON: Healing in germfree and conventional mice after tooth extraction. J. Oral Surg. 1966, 24: 239-246. (220, 221, 228). 139. Rr_rD, J.: Removal of impacted lower third molars with acute pericoronitis and necrotising gingivitis. B. J. Oral Surg. 1970, 7: 153-159. (225, 226, 228). 140. RUb, J., H. BAOGESEN & J. F. MJ~s Effect of the sulfa cones and suturing on the incidence of pain after removal of impacted lower third molars. J. Oral Surg. 1963, 21: 219-226. (219, 224, 228). 141. RUSSELL, L. T. & N. C. CHAgI_Oa"m: A comparison in methods of prevention of local alveolar osteifis, l. Oral Surg. I944, 30: 95-97. (227, 228). 142. SCHILLI, W., F. SCaARP & C. LANGE: Die trockene Alveole - - ein Problem der zahn~irztlichen Sterilisation? Dtsch. zahnaerztl. Z. 1967, 8: 1026-1029. (218, 225, 226, 228, 229, 237). 143. SCHROFF, J. & H. A. BAXTELS: Painful sockets after extractions. J. Dent. Res. 1929, 9: 81-88. (222, 228). 144. SCHULTZ, W.: D& Retraktion des Blut. gerinnsels und ihre Bedeutung flir die primiire Heihmg von Kieferknochen.

262 defekten. Thesis, Carl lJanser Verlag, Miinchen 1964, pp. 60--66. (221). 145. SCHtmTE, W.: Die antifibrinolytischeWirkung yon Apernyl| Dtsch. zahnaerztl. Z. 1971, 26: 863-870. (229, 237, 254). 146. SCHOLar, W. & A. G~W~,LT:Die fibrinolytische Aktivitiit des menschlichen Sl~eichels unter Beri~cksichtigung des Speichel-pHWertes. Dtsch. zahnaerztl. Z. 1964, 19: 59.3--601. (229, 237, 240). 147. SCtlULTE,W. & B. GOEtqS: Menses, Speichelfibrinolyse und Wundheilung. Dtsch. zahnaerztL Z. 1967, 22: 379-383. (229, 237, 252). 148. SCmJLTE, W. & B. SORO: Die fibrinolytische Aktivit~it des Speichels und des Blutes - - vergleichende Untersuchungen. Dtsch. zahnaerztl. Z. 1967, 22: 1101-1106. (229, 237, 240). 149. SEt.oN, H. M.: Accidents in exodontia, and how to avoid them. Dent. 1terns Interests. 1933, 55: 705-710. (226). 150. SHEh., W. E.: Cause and treatment of dry socket. J. A m . Dent. Assoc. 1943, 30: 289290. (223). 151. SHF.m~Y, S., A. P. FLETCrmR & N. ALr~AERSlO: Fibrinolysis and fibrinolytic activity in man. Physiol. Rev. 1959, 39: 343-382. (235, 251). 152. S~sot~, H. E.: Experimental investigation into the healing of extraction wounds in macacus rhesus monkeys. J. Oral Surg. 1960, 18: 391-399. (220, 221, 229). I53. S~aPSON, H. E.: Healing of surgical extraction wounds in macacus rhesus monkeys: I. The effect of burs. J. Oral Surg. 1961a, 19: 3-9. (220, 229). 154. SIMPsoN, H. E.: Healing of surgical extraction wounds in macacus rhesus monkeys: II. The effect of chisels. J. Oral Sllrg. 1961b, 19: 126--129. (220, 229). 155. S~4OSON, H. E.: The healing of extraction wounds. B. Dent. J. 1969, 126: 550-557. (221, 229). 156. St~CL,UR, J. A.: Factors involved in the production of painful slow healing operative lesions, with special reference to the so-called "dry socket". Dent. 1terns Interests. 1943, 65: 835-848. (223, 224, 225, 229, 237). 157. STEtCHELE, D. F. & H. J. HERSCttLEIN: Zur antifibrinolytischen Wirkung des Trypsin- Kallikrein - Inaktivators. Med. Welt. 1961, No. 42: 2170-2172. (236). 158. STEINI-IAI~, G.: Pathologisch anatomische Untersuchungen zur Heilung vort Zahnextractionswunden und ihre Kompli-

BIRN kationen bei Menschen. Paradentose (Berlin). 1932, 5: 121-126. (220). 159. SWANSON, A. E.: Reducing the incidence of dry socket: a clinical appraisal. J. Can. Dent. Assoc. 1966, 32: 25-33. (227, 228). 160. T^GNON, H. J. & M. L. PETEaMXtaN: Activation of proplasmin by a tissue frac~on. Proc. Soc. Exp. Biol. (N. Y.). 1949, 7 0 : 359-360. (236). 161. TICE, D. A. & M. H. WortTrI: Cellular damage associated with extracorporeal perfusion: Plasminogen activation and lysosomal enzyme activity. Surgery. 1968, 6 3 : 669-672. (236). 162. TILL, T.: BeriJchsichtigung der bakteriellen Gegebenheiten in der Mundh61e nach operativen Eingriffen. Schweiz. Monatsschr. Zahnheilkd. 1969, 79: 584-586. (228). 163. TmLETT, W. S.: The fibrinolytie activity of hemolytic streptococci. BacterioL Rev. 1938, 2: 161-216. (235, 237). 164. TILLErr, W. S. & R. L. GARNER: The fibrinolytic activity of hemolytic streptococci. J. Exp. Med. 1933, 58: 485-502. (235). 165. TODD, A. S.: Fibrinolysis autographs. Nature (Lond.). 1958, 181: 495--496. 166. T6rrELI, A.: Untersuchungen tiber die fibrinolytische Wirkung des Speichels. Dtsch. Stomatol. 1967, 17: 96-107. (229, 237, 240). 167. TSOCmYA, K.: Studies on the plasmic substances found in the oral and related tissues. J. Nihon Sch. Dent. 1964, 6: 158162. (237). 168. UNOXa, G.: Inflammation and its control. A biochemical approach. Lancet 1952, II: 742-746. (251). 169. VOGT, W.: Kinin formation by plasmin, an indirect process mediated by activation of kallikreiu. I. Physiol. (Loud.). 1964, 170: 153-I66. (248). 170. W~aTE, D. E.: "Dry socket" (localized osteitis). Pract. Dent. Monographs. Nov. 1957, pp. 5-27. (217, 220, 222, 223, 226). 171. W^LD, A.: Postoperative complications in exodontia: their treatment and prevention. Dent. Cosmos. 1932, 74: 72--77. (229). 172. WARREN, B. A.: Fibrinolytic activity of vascular endothelium. B. Med. Bull. 1964, 2 0 : 213-216. (243). 173. WEBSTER, ~[. F.: Kallikreins in glandular tissue. In: ERD6S, E. G. (ed.): Bradykinin, kallidin and kallikrein. Handb. exp. Pharmacol. Springer Verlag, Berlin 1970, 25: 131-155. (248).

ETIOLOGY AND PATHOGENESIS OF FIBRINOLYTIC ALVEOLITIS I74. WEBSTER, M. E. & I. INNER.FIELD: Interrelationship of human plasma kallikrein and plasmin in inflammation. Enzym. Biol. Clln. 1965, 5: I29-148. (248). 175. WERLE, E.: tiber den AktivitS.tszustand des Kallikreins der Bauchspeicheldriise und ihres 5usseren Sekretets beim Hund. Biochem. Z. 1937, 290: 129-134. (248). 176. WERLE, E., M. M. FORELL & L. MAIER: Zur Kenntnis der blutdrucksenkende Wirkung des Trypsins. Naunyn-Schmiedeberg's Arch. Exp. Pathol. Pharmakol. 1955, 225: 369-380. (2,18, 250). 177. WERLE, E. & F. PREISSert: Zur Frage der Identit~it von Kallidinogen und Bradykininogen, t:.lin, l.Vschr. 1956, 34: 1042. (248).

263

178. WERLE, E. & P. VON RODEN: 13ber da~ Vorkommen von Kallikrein in den Speicheldriissen und im Mundspelchel. Biochem. Z. 1936, 286: 213-219. (248). 179. WErtlm, E. & R. VOOEL: Ober die Freisetzung einer kallikreinartigen Substanz aus Extrakten verschiedener Organe. Arch. Int. Pharmacodyn. 1961, 131: 257-261.

(248). 180. WHITFmLn, A. J.: Use of thiamin chZor/de in the prevention of pain from dry sockets. I. Am. Dent. Assoc. 1941, 28: 450-453. (223, 229). 181. ZIMMER, M. A.: Dry socket: A clinical study and method of treatment. Dent. Cosmos. 1929, 71: 1204-1207. (223, 224, 225, 227).