Continued anticoagulation procedures

DEP.-\RTBIESTS

OF

IIOSl’lTAL, SCHOOLS

TORRASCE, OF

DENTISTRY

DENTISTRY, AND AND

RIEDICINE, THE

T’NIVERSITY

in oral surgery

.\NI) OF

SURGERY, C.tLIFORNIA

HARBOR

GENERAL

AT

ANGELES,

LOS

hlEDICINE

~Inticoagulants arc used in a numl,er of clinical settings for the prevention and trwtmvnt of thromboeml~olic disease. The oral surgeon is seeing au increasing number of these anticoagulated patients with oral and deutal disease. d technique is prescntcd which minimizes the normnticoagulated time for a patient requiring an oral surgical prowdurr. The twlmiquc wquires hospitalizat,ion and should br used only for patients who are in danger of thromboembolism.

0

ral anticoagulation is instituted on a chronic basis in a number of clinical situations. The oral surgeon increasingly is confronted with patients who are anticoagulated, and therefore he must arrive at an approach to hcmostasis which will not tbntlangclr the patient. Many patients such as those with prosthetic cardiac valves, might be in jeopartlv if not anticoagulated. Prosthetic valves, for instance, have been shown to adsorb plasma proteins.’ Following this adsorption, platelet adherence has been shown to occur,’ as well as activation of the intrinsic clotting system. These findings support the need for anticoagulants in those patients with valvular prostheses, in addition to tht ronvincing clinical data to be cited below. ‘I’hc following discussion is intended to review newer developments in the field of hemostasis, discuss thti use of oral anticoagulants and drug interactions, define various populations in which these drugs are used, and, finally, discuss an approach to the anticoagulated oral surgery patient. PLATELETS

Normal thrombosis begins after vesselin jury with vascular constriction.“” The endothclium must be tlisrupted, so that platelets can adhere to subendothelial connective tissue. The platelets swell and, by a not totally understood mechanism, release adenosine diphosphate (AD!?) which promotes further platelet aggregation and release of ADP.” Platelet aggregation is a calciam-dependent process,

448

Volume Number

40 4

Continued

anticoagulation

in oral surgery

449

and the mass of platelets formed is called the platelet “pl~g.“*~ This reaction can also be initiated by epinephrine and thrombin in vitro.“l The formation of the platelet plug is called primary hemostasis. The best and most simple test of platelet function is the bleeding time determination (normal, 6 to 9 minutes), which can be performed in the of&e or clinic. The bleeding time assesses only primary hemostasis ; hence, it will be abnormal only in pathologic states which alter the number or function of platelets. The platelet-aggregation process can be blocked by acetylsalicylic acid (aspirin).40 Since aspirin is a nonprescription drug that is commonly used for dental disease, it is frequently not listed in a drug-intake history. As little as three tablets (5 grains each) can raise the bleeding time twofold in otherwise normal persons.‘y The story is incomplete, however, as aspirin has been used for decades without causing observable postoperative hemostatic defects. The platelet plug appears to serve as a surface for the formation of a clot where the blood-coagulation factors are active. The clot and the platelet plug are necessary for effective hemostasis. This process is evident in patients with hemophilia in whom, because of lack of normal clot formation, rebleeding at sites of trauma occurs after the platelets have halted the initial bleeding. BLOOD-COAGULATION

There vated-the The

intrinsic

FACTORS

are two intrinsic

independent pathways by which and the extrinsic systems.

prothrombin

can be acti-

system

The intrinsic system is initiated when the plasma makes contact with a surface-active material, specifically, collagen. In vitro, glass can serve as the surfaceactive material. The contact activates factor XII, or the Hageman factor. The activated Hageman factor has proteolytic enzyme activity affecting factor XI (PTA, or plasma thromboplastin antecedent). 24 No calcium or phospholipid is required for these two reactions. The activated factor XI, in turn, activates factor IX (Christmas factor), also thought to be proteolytic enzymatic step.14 Calcium is a necessary co-factor in this reaction. The next step is the interaction of activated factor IX with factor VIII (AHG or antihemophilic globulin), factor X ( Stuart-Prower factor), calcium, and phospholipids to yield an activated factor X. The mechanism is unclear, but factor VIII appears to serve as a co-factor in activation of factor X by factor IX.” The

extrinsic

system

This system bypasses the reactions of the intrinsic pathway. defined tissue factor, a lipoprotein, is involved in this mechanism. factor VII form a complex which, w&h calcium, activates factor Prothrombin

activation

and

clot

An as yet unThis factor and X.25

formation

Both extrinsic and intrinsic systems, therefore, activate factor X. The activated factor X combined with factor V, calcium, and phospholipid converts prothrombin to thrombin.13 Thrombin then activates fibrinogen by enzymatically cleaving it into fibrin monomers. These monomers are transaminated by factor

Oral October,

CONTACT

SYSTEM

ACTIVATION FACTOR

XII

Surface

Tissue

‘ma

PROTHROMBIN CONVERSION

Prothrombln

2’Cyri

FIBRIN FORMATION

Fibrinogen

Thrombin -

FSF

*

Thrombin

Fibrin

monomer

Thrombin Ca++

l

FSF*

FSF* Fibrin

Thromb.

1.

‘LU

1: l-37,

coagulation

1972,

Factor

OF X

FIBRIN STABILIZATION

Piy.

Slug. 1975

Grune

mechanism. & Stratton,

monomer

-

Cross-linked

(After Nemcrson and New York, N.Y., publisher.)

Pitlick:

fibrin

Prog.

Hemostasis

XI11 (fibrin-stabilizing factor), yielding a covalent bonded cross-linked fibrin which ha,s increased mechanicdal strength.l’ Factor XIII is activated by thrombin ant1 calcGum. ,2 rerir\v of the above data is seer1 in Fig. 1. ORAL

ANTICOAGULANTS

The eoumarin anticoagulants arc water-soluble drugs which are well absorbed in the small intestine. They are transported in a loose bond with albumin and, therefore, distribute to the albumiii space. They can cross the placenta and are found in human mammary secretions. They are degraded by the cndoplasmic reticulum in the parenchymal ~11s of the liver to products which are again bound to albumin and excreted by the kidney. The half-life is related to the dcgradatiou rate, which has been shown in one study to vary from 15 to 56 hours.” Vitamin K, one of the fat-soluble vitamins, is found in small amounts in the diet and is also synthesized by intestinal flora. After being absorbed and transported by the portal circulation, it is a primary factor in the formation of four procoagulants. These arc factors VII, IX, and X and prothrombin. Its mode of action is not known, but it is t,hought to act at the ribosomal level, where the factors are synthesized, perhaps by the addition of a carbohydrate moiety to them.7 The coumarins inhibit the action of vitamin K in the production of active vitamin K-dtpendcnt factors, perhaps blocking the addition of the carbohydrate group. Recent data have shown that immunologically detectable factors VII, IX, X, and prothrombin arc’ produced, but these have no procoagulant activity.“’ By referring to the initia.1 discussion, it readily will be noted that both the intrinsic and extrinsic: pathways will be affected by the coumarins. Indeed, both the prothrombin time (PT) and the partial thromboplastin t,ime (PTT) will be prolonged. The PT assessesthe c~xtrinsic: pathway by adding a tissue factor and

Volume Number

Continued

40 4

anticoagulatio?L

in oral surgery

451

calcium to plasma. If factors X and VII or prothrombin are diminished by the use of coumarins, the PT will be prolonged. The normal PT is usually 12 to 15 seconds. The PTT assesses the intrinsic pathway where only phospholipid and calcium are added. If factors IX and X or prothrombin are diminished, it will be prolonged. The normal PTT is usually 25 to 34 seconds by the activated method. By convention, the PT was utilized to follow the therapeutic effects of the coumarins, mainly because it was the only test available when the coumarins were first introduced. The usual therapeutic range is twice to two and one half times the control level for the individual patient. Discussions of the proper methods of using these drugs and management of toxicity have been reviewed elsewhere.6,7 Besides vitamin K, which will totally reverse the anticoagulation produced by the coumarins in 24 to 48 hours, fresh frozen plasma also contains the vitamin K-dependent procoagulants and can be utilized for control of side effects or lowering of the PT into a therapeutic range. DRUG

INTERACTIONS

WITH

COUMARINS

Since numerous drugs interact with the coumarins to adversely affect their therapeutic effectiveness and potential toxicity, any patient being treated with coumarins should not be started on other drugs unless the potential interactions are defined. The absorption of the coumarins or vitamin K can be disturbed by certain agents. Absorption of bishydroxy coumarin, which is the least well-absorbed coumarin, can be enhanced by hepatobarbital and allopurina1.l Cholestyramine can bind vitamin K, thus enhancing the effect of the coumarins.3” Other agents can affect the binding of coumarins to albumin. If an agent displaces coumarin, it will increase the level of free drug in the serum and therefore enhance its effect. Agents in this group include A.S.A., Dilantin, phenylbutazone, Indocin, and Atromid.ls There are agents which will increase the biotransformation of the coumarins by increasing hepatic microsomal activity. The most important agents in the group are barbiturates and glutethimide.‘” It is easily discerned that this will diminish the activity of coumarins, necessitating higher dosa.ges. Quinidine can enhance the affinity of hepatic receptors for coumarins, thus enhancing their effect. On the other hand, oral contraceptives increase the synthesis of the vitamin K-dependent liver factors which antagonize the effect of the coumarins.7 Finally, any drug that affects platelet function, such as A.S.A., will enhance any bleeding tendency caused by the coumarins. HEPARIN

Heparin has been used as an anticoagulant for almost 40 years. It is a mucopolysaccharide and is normally present in the human mast cell. It was thought that heparin might keep blood fluid, but it has been shown that minute amounts activate the lipoprotein lipase, which is partly responsible for clearing chylomicrons. No anticoagulant activity, however, is demonstrated for this endogenously produced heparin. On the other hand, pharmacologic dosesof heparin are known to be a powerful

iInti(~oitgul;l~~t, workitrg OII tllc> l)roc~oagulallt IIeparin, in c.ollCjnll~tion \vith a co-factor,

systenl by a number of mechanisms. retartls thromhin activity and therefOIY’ I)Yc!\‘f?lltS fihriHO@Il ~l~~g~ilc.l:lti~~l~. I”. ” Hcparin inhibits prothrombin conyersion, possibly by inhihitioll of factor V activit,y.:‘4 In addition, even in small doses, heparin enhances thr activity of a naturally occurring inhibitor of factor X.4’ Heparin is used principalI>as an acute anticoagulant, since its activity is immediate aftc>r intrarctnous aclministration. The activity noted against factor X has let1 to trials of low tloscs of hcparin ill caertain high-risk patients in danger of thrombormholi~ (IiS~iZRe.” I’rotaminc sulfate is used in situations in which rapid reversal of the anticoagulant activity of heparilj is necessary. It c*ombines strongly with heparin to form a stable salt ; howe~t:r, when given in excess, it has its own anticoagulant activity by inhibiting the thromhin-fibrinogen interaction. Anticoagulants arc used in a nnmbcr of clinical settings, principally for the prcrentiorr ant1 treatment ot’ thromboembolic disease. Heparin, to reiterate, is used for acute anticoagulation where immediate activity is necessary, as in patients with pulmonary cmbolic disease. The coumarins are used to substitute for hcparin after effective anticoagulation is obtained. However, they can be used as primary agents when acute anticoagulation is not mandatory. Cardiac diseases are among the major indications for anticoagulation. Since the study by- IYright and associat&’ showing decreased mortality in myoeardial infarction \vith anticoagulation, multiple studies have attempted to confirm this. In one of the largest studies by a T’eterans Administration Cooperative Study Group,“!’ mortality was not curtailed. However, thromhoembolic complications, including l)ulmonary alld wwhral cnrboli, were significantly diminished. Atria1 fibrilIation and c.ongestive heart failure, when either is chronic, are other indications for anticoagulation. Furthermore, anticoagulation is a standard regimen for those patients in whom prosthetic heart valves have been placed. It is clearly shown that these patients benefit significantly from their use.!’ Of interest is the more recent use of antiplatelet agents, such as aspirin, in addition to the coumarins.37 Deep-vein thrombol~hlcbitis is treated with anticoagulants to prevent further clot extension and pulmonary emboli. In hospitalized anticoagulated patients the incidence of pulmonary embolic disease is significantly rcduced.‘l There is no argument over the USC of anticoagulants in person with established pulmonary cmbolic disease. The data in one study were so convincing that no further controlled studies have been conducted.” Finally, patients with occlusirc cerebrovascular disease with transient ischemic attacks were benefitted by alltieoagulants in that the attacks were ameliorated and the incidence of strokes dccrcascd2” ANTICOAGULANTS

IN ORAL

SURGERY

It is estimated that mor(’ than OIIC million patients are now receiving anticoagulants. I2 Because of this large number, most oral surgeons at some time arc confronted with patients requiring elective or mandatory oral surgical procedures.

Continued

anticoagulation

in oral surgery

453

There are conflicting reports in both the medical and dental literature concerning the approach to treatment of these patients.3y 5, lo, 2X>23,41 Authors report both success and failure in maintaining patients who require oral surgical procedures on continuous anticoagulant therapy. The dilemma is further compounded by reports that patients with prosthetic valves have died suddenly of thromboembolism when their anticoagulant therapy was stopped abruptly.” In fact there is no standard therapeutic approach to these patients. It appears that each patient’s treatment plan is tailored by his cardiologist, internist, and dentist. What, then, are the risks involved in discontinuing the anticoagulation therapy in each of the previously mentioned groups of patients on continuous therapy? DISCONTINUATION

OF ANTICOAGULANT

THERAPY

For all groups there is a small but significant risk of sudden thrombotic and embolic complications if the anticoagulant therapy is stopped abruptly. This may not be related to what has been called the “rebound phenomenon” but may represent events in patients who have an underlying thrombotic tendency.31 Keeping this in mind, and with proper warning to the patient, one can withdraw anticoagulants for a short time from patients with resolving thrombophlebitis, previous myocardial infarctions, compensated congestive heart failure, and controlled atria1 fibrillation without adding significantly to the risk of thromboembolism. Consultation with the patient’s internist, careful monitoring of daily prothrombin times after discontinuation of the coumarin, atraumatic surgery, use of gelfoam and sutures, and prompt reinstitution of coumarin postoperatively are essential to decrease the risks of hemorrhage or thrombosis. Daily determination of prothrombin time are necessary since the variability of response to coumarin among different persons makes accurate prediction of the prothrombin level difficult. Patients with carotid artery disease and transient ischemic attacks must be cautioned that the transient ischemia of the central nervous system may recur while they are not anticoagulated. Because of the ongoing stimulus for thrombosis formation, the group of patients most in danger of thromboembolic episodes are those with prosthetic heart valves. Abrupt discontinuation of anticoagulants in these patients has led to fetal consequences2*9 HEPARIN-COUMARIN

METHOD

One approach to the problem has been used successfully at Harbor General Hospital. It is based on the rationale that if the initial clot in the surgical site is of good quality and is maintained for 12 to 18 hours, subsequent postoperative bleeding will be minimal and the healing more rapid despite resumption of anticoagulation. The technique substitutes parenteral heparin, with a half-life of 4 hours, for coumarin, which in our experience has required 48 to 96 hours to reverse without using vitamin K. The patient’s coumarin is stopped 24 hours prior to admission to the hospital and heparin therapy is instituted upon admission. The effectiveness of coumarin therapy on the coagulation mechanism is measured by the prothrombin time. The effect of heparin on the coagulation mecha-

Oral October,

Surg. 1975

-_1--

4/6/74 Date PT

18.5

PTT

Heparin

4/a/74

Admission

dosage

4/7/74

sec./

15

Surgery

sec./

12.5

sec.

12.5

35

sec./

52

sec./

28

sec./

32

sec.

34

sec.

35

sec.

5,000

U.

q.6h.

sec.

sec./

12

5,000

12

U.

q.4h.

sec.

Last

dose

8

hours

prior

to

4/l

3174

surgery Coumadin

dosage

None

4/9/74

None

4/10/74

7.5

4/l

l/74

mg.

4/

post-operatively

12174

Discharge

12

sec./

13.5

sec./

14

sec./

17

sec./

18

sec./

12

sec.

12.5

sec.

12

sec.

12

sec.

12

sec.

45

sec./

62

sec./

45

sec./

50

sec./

35

sec.

32

sec.

29

sec.

32

sec.

5,000 U. started 10

q.4h. this

5,000

5,000

U.

q.4h.

4,000

U.q.4h.

D/C

a.m.

mg.

10

Fig. .S. Example of carious

U. q.4h.

-

mg.

of heparin-Coumadin

7.5

mg.

medication

5 mg.

schedule

of a patient

5

mg.

undergoing

removal

teeth.

nism is measured by the activated partial thromboplastin time or Lee White clotting time. Uespite the fact that coumarin affects the activated partial thromboplastin time to a certain extent, we have encountered no difficulty in establishing a satisfactory level of anticoagulation with heparin. The Owren prothrombin or proconrertin test would circumvent the problem, but these tests are not readily available. As soon as the prothrombin level has returned to normal, as assessed by normalization of the prothrombin time just prior to a dose of heparin, the patient is scheduled for the surgical procedure. Heparin therapy is discontinued 8 hours preoperatively. The prothrombin time and the activated partial thromboplastin time are again measured, and if they are found to be in normal range the procedure is carried out. Heparin therapy is recommended 12 to 24 hours postoperatively, depending on the extent of the surgical procedure. As mentioned earlier, we believe that it is necessary to provide a certain amount of time postoperatively for an adequate clot to form at the surgical site. The 12- to 24-hour period is an arbitrary time period which we have found to be successful. Coumarin is reinstituted on the night of the operation, as it will take 48 to 96 hours to reduce effectively the patient’s procoagulant levels to a therapeutic range. When this has been achieved, heparin therapy is discontinued and the patient is discharged. In effect, the total time the patients remain without anticoagulation ranges from 18 to 24 hours, as opposed to 3 to 4 days with the traditional method of discontinuing and reinstituting coumarin. Although this approach dots not, eliminate all the risk of thromboembolism in these patients, the relatively short time span of normal coagulative ability should reduce the incidence greatly. Perhaps maintenance, throughout, the day of surgery, with low

Volume Number

Cmtinued

40 4

doses of subcutaneous heparin hemostasis and anticoagulation. CASE

a&icoagulation

may be a reasonable

ilp oral surgery

compromise

between

455 good

REPORT

A 42.year-old Negro man was referred to the oral surgery clinic for diagnosis and treatment of dental pain. Examination revealed four carious teeth. One year earlier the patient had recovered from subacute bacterial endocarditis with a grossly insufficient aortic valve. Three months later he received a Starr-Edwards aortic prosthetic valve replacement. Present medications included 5 mg. of Coumadin daily. Admission to the hospital was scheduled and the patient was instructed to omit his Coumadin the night before he entered the hospital. Intravenous heparin therapy was instituted on admission. On the third hospital day the teeth were removed under local anesthesia, following the omission of two doses of heparin (8 hours preoperatively). (See Pig. 2.) The patient received 7.5 mg of Coumadin the night of the surgical procedure. Heparin was reinstituted on the evening of the first postoperative day. On the fifth postoperative day t,he patient was discharged after an uneventful postoperative course. This particular approach is recommended only for the high-risk patient on anticoagulants, as it is complex, requires hospitalization, and calls for the assistance of the patient’s internist or cardiologist. To date, seven patients have undergone procedures ranging from full-mouth extractions to removal of four impacted third molars. There were no episodes of thromboembolism and only one episode of postoperative oozing that required discontinuation of heparin therapy for an additional 24 hours. The average length of hospitalization was 9 days. Although only patients with prosthetic valves have been treated by this technique, it would be applicable to any oral surgery patient on continuous oral anticoagulant therapy who is in danger of thromboembolism because of his disease.

SUMMARY

Newer developments in the field of hemostasis, the use of anticoagulants, and interactions of the oral anticoagulants with other drugs have been discussed. Various populations requiring continuous anticoagulation therapy have been defined. The approach to management of these patients is divided. Both maintenance of continuous anticoagulation therapy and discontinuation of the anticoagulants for oral surgical procedures have met with success.The management of a particular patient appears to be dictated by personal experience of the attending physician and dentist. The greatest risk of thromboembolism resulting from discontinuation of anticoagulation is in the postprosthetic valve patient. A method of utilizing heparin and coumarin for maintenance of the patient’s anticoagulation for all but a short time for oral surgery procedures has been presented. This technique, while applicable to all patients on continuous anticoagulation therapy, is complex and requires interdisciplinary cooperation ; hence, we do not recommend it for any but the patient with the greatest risk of thromboembolism. We wish

to thank

Herman

Kattlove,

M.D.,

for

his help

in reviewing

this

manuscript.

REFERENCES

1. Aggeler, P. M., and O’Reilly, P. A.: Effect of Heptabarbital on the Response to Bishydroxy Coumarin in Man, J. Lab. Clin. Med. 74: 229, 1969. 2. Akbarian, M., Austin, W. G., Yurchak, P. M., and Scannell, J. G.: Thromboembolic Complications of Prosthetic Cardiac Valves, Circulation 37: 826-831, 1968. 3. Askey, J. M., and Cherry, C. B.: Thromboembolism Associated With Auricular Fibrillation; Continuous Anticoagulant Therapy, J. A. M. A. 144: 97, 1950.

Oral October,

Surg. 1975

4. Barritt, 1~. W., and Jordan, 8. C.: Anticoagulant Drugs in the Treatment of Pulmonary Embolism: A Controlled Trial, Lancet 1: 1309, 1960. 3. Behrman, H. tJ., and Wright, I. S.: Dental Surgery Inming Continuous r\nticoagulxnt Theranv. J. Am. Dent. Assoc. 62: 172. 1961. 6. Coon, W. IV., and Willis, I’. W.: Hemorrhagic Complications and Anticoagulant Therapy, Arch. Int,. Med. 133: 386, 1974. 7. Deykin, D.: Warfarin Therapy, N. Engl. 3. Med. 283: 691, 801, 1970. 8. Deykin, D.: Emerging Concepts of Platelet Function, N. Engl. J. Med. 290: 144, 1974. 9. Duvoisin, G. E., Brandenburg, R. O., and McGoon, D. C.: Factors Affecting Thromboem holism Associated With Prosthetic Heart Valves, Circulation 35: 70-76 (Supp. I), 1967. IO. Frank, B. W., Dickenhaus, D. W., and Claus, E. C. : Dental Extractions in the Presence of Continual Anticoagulant Therapy, Ann. Int. Med. 59: 911, 1963. 11. Harris, W. N., Salzman, E. W., and DeSanctis, R. W.: The Prevention of Thromboembolic Disease by Prophylactic Anticoagulation: A Controlled Study in Elective Hip Surgery, J. Bone Joint Surg. 49: 81, 1967. 12. Jacques, L. B.: Anticoagulant Therapy, New York, 1965, Charles C Thomas Publisher, p. vii. 13. Jobin, F., and Esnouf, M. P.: Studies on the Formation of Prothrombin Converting Complex, Biochem. J. 102: 666, 1967. 14. Kingdon, H. S., Davie, E. W., and Ratnoff, 0. D.: The Reaction Between Activated Plasma Thromboplastin Antecedent and Diisoprophylphosphofluoridate, Biochem. J. 3: 166, 1964. Interactions With Coumarin Anticoagulants, 15. Koch-Weser, J., and Sellers, E. M.: I)rug N. Engl. J. Med. 285: 487, 547, 1971. 16. Lewis, J. H., and others: Applications of Continuous Flow Electrophoresis to the Study of Blood Coagulation Proteins and the Fibrinolytic System, J. Clin. Invest. 37: 1323, 1958. 17. Lorand, L., Konishi, K., and Jacobsen, A.: Transpeptidation Mechanism in Blood Clotting, Nature 194: 1148, 1962. 18. Lyttleton, J. W.: The Antithromboin Activity of Human Plasma, Biochem. J. 58: 8, 1954. 19. MacDonald, M. G., Robinson, D. S., Sylvester, D., et al.: The Effects of Phenobarbital, Chloral Hydrate, and Glutethimide .4dministration on Warfarin Plasma Levels and Hypoprothrombinemic Responses in Man, Clin. Pharmacol. Ther. 10: 80, 1969. 20. MacFarlane, K. G., Brygs, R., Ash, B. J., and Denson, K. W. E.: The Interaction of Factors VIII and IX. Br. J. Hematol. 10: 530. 1964. 21. Madras, I’. N., Morton, W. A., and Petscheck, H. E.: Dynamics of Thrombosis Formation, Fed. Proc. 30: 1665, 1971. 32. Marcus, A. J.: Platelet Function, N. Engl. J. Med. 280: 1213, 1969. 23. Millikan, C. H.: Reassessment of Anticoagulant Therapy in Various Types of Oeclusivc Cerebrovascular Disease, Stroke 2: 201, 1971. 24. Nemerson, Y., and Pitlmk, F. A.: The Tissue Factor Pathway of Blood Coagulation, Prog. Hemostasm Thromb. 1: l-37, 1972. 25. Nemerson, Y.: The Reaction Between Bovine Brain Tiasuc, Factor and Factors VTT and X, Biochemistry 102: 666, 1967. 26. Nicholaides, A. N., and others: Small Doses of Subcutaneous Sodium Heparin in Preventing Deep Venous Thrombosis After Major Surgery, Lancet 2: 890, 1972. 27. @Reilly, R. A., Aggeler, I’. M., and Leong, L. S.: Studies on Coumarin Anticoagulant Drugs, Pharmacodynamics of Warfarin in Man. J. Clin. Invest. 42: 1542. 1963. 28. O’Reilly, R. A. : The Pharmacodynamics of the &al Anticoagulant Drugs,‘Prog. Hemostasis Thromb. 2: 176. 1974. 29. Quick, A. J.: Salicylates and Bleeding, the Aspirin Tolerance test, Am. J. Med. Sci. 252: 265, 1966. 30. Salzman, E. W.: Nonthrombogenic Surfaces: Critical Review, Blood 38: 509, 1971. 31. Salzman. E. W.. Leusler. P. C.. and Levine. L.: Cvclic 3’ 5’ Adenosine Mononhosnhate in Human Blood Platelets, ‘IV. Regulatory Role of cyclic AMP in Platelet Function, Ann. N. Y. Acad. Sci. 206: 61, 1972. 32. Schwartz, S. I.: Principles of Surgery, New York, 1969, McGraw-Hill Book Company, Inc., p. 105. 33. Scoop, I. W., and Fredricks, 11.: Dental Extractions in Patients Undergoing Anticoagulant Therapy, ORAL SURG. 11: 470, 1953. 34. Seegers, W. H., and Marciniah, E.: Autoprothrombin C in Irregular Blood Clotting, Thromb. Diath. Haemorrh. 8: 1, 1962. 35. Shira, R. B., Hall, R. J., and’ Guernsey, L. H.: Minor Oral Surgery During Prolonged Anticoagulant Therapy, J. Oral Surg. 20: 93-99, 1962. 36. Shulman, I.: Vascular Factors in Hemostasis, Ann. Rev. Med. 14: 339, 1962. 37. Sullivan, J. M., Harkin, D. W., and Garlin, R.: Pharmacologic Control of Thromboembolic Complications of Cardiac Valve Replacement, N. Engl. J. Med. 279: 576, 1968. 38. Vesell, F. S., Passananti, G. T., and Greene, F. E.: Impairment of Drug Metabolism in Man by Allopurinol and Nortriptyline, N. Engl. J. Med. 283: 1484, 1970. IS,

-I

~~~

Volume Number

40 4

Continued

an ticoagulatiovL in oral surgery

457

39. Veterans Administration Cooperative Study Group : Anticoagulants in Acute Myoeardial Infarction, J. A. M. A. 226: 724, 1973. 40. Willis, A. C.: Biosynthesis of Prostaglandins E? and F, a generates Labile Material Which Induces Platelet Aggregation, Fourth International Congress on Thrombosis and Hemostasis (Absts.), Vienna, 1973, Vienna Gistel et Cie, p. 79. 41. Wright, I. S., Marple, C. O:, and Beck, D. F.: Myoeardial Infarction, Its Clinical Manifestations and Treatment With Anticoagulants : A Study of 1,031 Cases, New York, 1954, Grune & Stratton, Inc. 42. Yin, E. T., Wessler, S., and Stall, P.: Biological Properties of the Naturally Occurring Plasma Inhibitor to Activated Factor X, J. Biol. Chem. 246: 3703, 1971. 43. Ziffer, A. M., S’copp, I. W., Beck, S., Baum, S., and Berger, A. R.: Profound Bleeding After Dental Extractions During Dicumerol Therapy, N. Engl. J. Med. 266: 351, 1957. Beprint requests to : Dr. Steven M. Roser Harbor General Hospital 1000 West Carson St. Torrance, Calif. 90509

Continued anticoagulation in oral surgery procedures.

Anticoagulants are used in a number of clinical settings for the prevention and treatment of thromboembolic disease. The oral surgeon is seeing an inc...
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