Fibrinolysis: A possible factor in the control of postoperative hemorrhage in the patient with hemophilia

oral medicine Editor:

ALVIN

L. MORRIS,

D.D.S., Ph.D.

Vice-President for Administration University of Kentucky Lexington, Kentucky 40506

Fibrinolysis: A possible factor in the control of postoperative hemorrhage in the patient with hemophilia R. L. Brcntp, Major, US& Colonel, USAF (DC)“” W&FORD LACKLAND

HALL AIR

USAF

MEDICAL

FORCE

BASE,

(DC),# and X. C. Kolodny, CENTER, TEXAS

A peripheral view of the physiologic and pathologic aspects of fibrinolysis as it may relate to postoperative hemorrhage in the hemophilia patient. The authors discuss the efficacy of epsilon-aminocaproic acid therapy in reducing the amount of factor VIII needed to maintain postoperative hemostasis.

E

xcessive hemorrhage is an ever-present problem in the surgical treatment of the patient with hemophilia. Occasionally, it may also be encountered in the hematologically “normal” patient. This article will attempt to explore the possible causes of excessive or pathologic fibrinolysis as it may relate to postoperative bleeding after first describing what is thought to be the normal fibrinolytic system.

PHYSIOLOGY

OF FIBRINOLYSIS

Blood coagulation, with its resulting deposition of fibrin, is one of the most common and yet complex of the biologic processes. Not only does circulating plasma have the ability to form fibrin, but it also has a fibrinolytic system for its dissolution. Fibrin, the product of the coagulation mechanism, is being deposited continually on all vessel walls. Nevertheless, the patency of the vasculaturc is maintained by circulating fibrinolytic enzymes.lW3 The opinions or assertions contained in this paper are those of the authors and are not to be construed as official or as reflecting the views of the Air Force. *Oral Surgeon, Dental Sciences Branch, USAF School of Aerospace Medicine, Brooks Air Force Base, Texas. Formerly Resident in Oral Surgery, Wilford Hall USAF Medical Center, Lackland Air Force Base, Texas. **Chairman, Department of Oral Surgery.

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The fibrinolytic mechanism may be described as a. system of activators that acts on plasminogen, a relatively inactive proteolytic enzyme, resulting in the formation of an active proteolytic enzyme called plasmin. The majority of the circulating plasminogen is probably produced in the liver, although it has been reported that eosinophils can synthesize and transport it. The conversion of plasminogen to plasmin occurs in plasma as well as with the strands of a clot.“. 5 Although the activators of plasminogen are highly specific enzymes, they are found in a.t least trace amounts in all body fluids, including urine, the gingival crevice and saliva, lysosomal granules of granulocytes, and the endothelial cells of capillaries, veins, and pulmonary arteries. The activator substance in the endothelial cells is thought to be released in response to vasoactive stimuli. Also, there are activators of bacterial origin which include streptokinase and staphylokinase.6 The activators of plasminogen are regulated by naturally occurring plasma inhibitors, while plasmin activity is controlled by circulating antiplasmins which are thought to be in the form of alpha globulins. There are synthetic compounds, such as epsilon-aminocaproic acid (EACA) , para-aminomethylcyclohexane, and para-aminomethylbenzoie acid, which also inhibit activation of plasminogen.’ Because of a physiologic dominance of the activators over the inhibitors, the fibrin monomer linkages are split continually by plasmin, thus preventing a pat,hologic intravascular coagulation. It is also interesting to note that the end products of this fibrin hydrolysis may contribute additionally to an existing bleeding tendency in that they have been shown to exhibit strong anticoagulant properties.* PATHOLOGY

OF FIBRINOLYSIS

The fibrinolytic mechanism can be pushed out of equilibrium by multiple factors, such as seen in the therapeutic use of plasminogen activator substances. It is well known that therapeutic doses of the “kinases” and even aspirin can cause a bleeding diathesis. Also, the excessive release of endogenous activator substance as seen related to tissue anoxia, increased body temperature, acute infection, shock, extensive surgical procedures (particularly of the lung), and the release of urokinase from a metastatic prostatic carcinoma increase the level of circulating activator substance. As many pressor amines are known to increase fibrinolytic activity, it has been suggested that stress fibrinolysis may be mediated through catecholamine release, although the exact mechanism is unknown. These excessive amounts of activator substance overwhelm the normal plasmin inhibitor mechanism, producing sustained high levels of plasmin for long periods of time.“-‘” Pathologic fibrinolysis may also be manifest by an impairment of the inhibitory mechanism, as seen in the patient with liver disease. The patient with impaired liver function cannot clear the normal levels of circulating plasminogen activator substance, and thus the balance is again tipped in favor of excessive fibrinolysis and an increased bleeding potential,

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It has been reported that clotting factors V, VIII, and IX are susceptible to the proteolytic effects of plasmin and thus would compound its anticoagulant potential. Factor XIII is thought to catalyze the transamination between fibrin polymers, bonding them together, to increase the structural integrity of the clot and thus rendering it more resistant to the action of the fibrinolysins. Thus, pathologic processes decreasing factor XIII may also be the basis of an unbalanced equilibrium resulting in excessive fibrinolysis.15 CASE REPORT A Zl-year-old Latin American man was admitted to the Oral Surgery Service of Wilford Hall Medical Center for removal of four premolars prior to the initiation of orthodontic treatment. The teeth were to be removed with the patient under intravenous sedation and local anesthesia. This young man and his brother are well known to our service as hemophiliacs. The patient had required an extended period of antihemophilic globulin (AHG) therapy following the removal of impacted third molars early in 1971. Other than multiple hospitalizations associated with hemarthrosis and lacerations and following tooth extraction, the past history and review of systems were noncontributory. The physical examination was essentially unremarkable, except for a healing wound of the left great toe, secondary to a lawn mower accident, and obvious crowding of the maxillary and mandibular teeth. Laboratory data, consisting of complete blood count, urinalysis, and chest radiographs were within normal limits. The VDRL was nonreactive. Preoperative partial thromboplastin time (PTT) was 60 seconds versus a control of 32. The factor VIII assay indicated an activity of 7.5 per cent of normal. The patient’s sensitivity to AHG was read as negative. Hospital

course

We decided to remove the teeth from the right maxilla and mandible, using our past regimen for patients with hemophilia. This consisted of an initial preoperative dose of AHG, followed by coverage for approximately one week postoperatively, at which time the medication was discontinued and the patient observed for recurrence of bleeding. The factor VIII level should be raised to at least 50 per cent activity immediately before the surgical procedure and then allowed to decrease to between 20 to 30 per cent activity for the remainder of the recovery period. The initial elevation to 50 per cent activity is higher than necessary for hemostasis but is thought by hematologists to tie up much of the circulating antibody present from previous AHG therapy. It is speculated that hemostasis and healing will have progressed to a point where, by the time the antibody titer again returns to normal, bleeding will not be a problem.% 17 On the second hospital day, the patient was given 2,534 units of AHG preoperatively (calculated by the hematologist), which decreased his preoperative PTT to 42/32 and increased his factor VIII activity to 52 per cent. The indicated teeth were removed by a standard forceps technique with the patient under intravenous sedation and local anesthesia. The patient tolerated the procedure well and was returned to the ward with gauze pressure packs in place. On the first postoperative day the PTT was 49/39 with a factor VIII activity of 37 per cent. On the second day PTT was 54/37 with a factor VIII of 17 per cent activity. On the third day, the PTT was 50/39 and the factor VIII activity was 21 per cent. During the postoperative period treatment consisted of 388 units of AHG intravenously every 6 hours, a dental soft diet, and analgesics which did not contain aspirin. This treatment was discontinued after 6 days without recurrent bleeding. The patient was discharged to his home for one week, after which time he was readmitted for the extraction of the corresponding teeth on the left side of the mouth. At the time of the second admission, the patient’s PTT was 91/39 with a factor VIII activity of less than 2 per cent. In contrast to the previous admission, the patient was given not only a preoperative dose of AHG (2,444 units intravenously) but, in addition, received a

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loading dose of epsilon-aminocaproic acid (Amicar), 5 Gm. by mouth. Postoperatively, AHG was not given. The postoperative PTT was 64/39 with a factor VIII activity of 23 per cent. The follow-up treatment consisted of one tablespoon of Amicar (3.75 Gm.) by mouth four times a day, a dental soft diet, and aspirin-free analgesics. The patient was discharged on the sixth postoperative day with no evidence of recurrent bleeding. He was continued on oral Amicar as an outpatient for an additional 5 days.

DISCUSSION

It seems reasonable to assume that many of our postoperative bleeding problems may be attributed to interference with the normal fibrinolytic balance of the oral tissues. The injection of a catecholamine in the local anesthetic, followed by the mechanical trauma to the operative tissues, compounded by potential wound sepsis by oral cocci and their “kinases,” may all contribute to an exaggerated fibrinolytic response.18-20 It is possible that a considerable degree of postoperative bleeding, usually attributed to epinephrine reversal, may in fact be caused by prolonged activator activity resulting from the direct effect of the catecholamine on the endothelial cells of the local capillary bed.‘l, 22 It follows that the more traumatic the surgical procedure, the greater the inflammatory response. An increase in the inflammatory cell infiltrate would, in turn, increase the amount of proteolytic enzyme, including fibrinolysin, that is expelled into the surrounding tissues. All of these factors tend to aggravate the already difficult task of achieving postextraction hemostasis in the person with hemophilia. With this in mind, we have adopted the following approach in the management of our hemophilic patients. We are now using a plasminogen inhibitor (Amicar) in conjunction with AHG therapy. This use of EACA in the control of bleeding in hemophiliacs is well documented in the literature.23-28 It has also been reported that preoperative hypnosis decreases that postoperative bleeding in patients with hemophilia.27 It appears that there is a relationship between emotional stress and fibrinolysis, which supports the contention that the control of fear and anxiety may, in itself, tend to reduce the lysis of the early clot. In this vein, we believe that sedation is indicated in these patients while a general anesthetic may not be merited. Opinions of different investigators vary as to the need for preoperative antibiotic coverage to reduce the incidence of postoperative sepsis. We do not routinely administer antibiotics preoperatively to our hemophilic patients.29, 30 We do not think that it is normally necessary to pack the extraction sites with hemostatic materials postoperatively. Absorbable gelatin sponge (Gelfoam) ) oxidized cellulose (Surgicel) , and the use of stents and resorbable sutures may increase the local inflammatory response and, with it, provide an increased stimulus for fibrinolysis. Postoperative analgesics containing aspirin are also to be avoided.31-3” The patients are placed on diets that vary from liquid to dental soft. On the third postoperative day any sutures placed during the surgical procedure are removed, while the diet is maintained to approximately the fifth postoperative

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day. These patients can usually be discharged after the fourth postoperative day, with their medications and soft diet being continued at home. SUMMARY

We have attempted to describe some of the more recent thoughts concerning fibrinolysis and how it may contribute to postoperative bleeding. We have begun to use epsilon-aminocaproic acid (EACA) preoperatively in our hemophilic patients, following the lead of Reid and others.27 The use of EACA usually produces a firm, elastic clot with normal, rapid healing of the area. This is in contrast to the friable, loose, slowly forming clot usually seen in the person with hemophilia. EACA thus decreases‘considerably the amount of antihemophilic globulin (AHG) necessary during the postoperative period. The attending benefits are reduced cost to the patient per hospitalization and a decrease in the risk of hepatitis and immunologic resistance usually seen after repeated, prolonged regimens of AHG therapy. The article.

authors

wish

to thank

Mrs.

Julie

Minus

for

her

assistance

in the preparation

of this

REFERENCES

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H. C.. and others: The Effect of Eosilon-Aminocaoroic Acid on the Healing of 25. Doku. Extraction VVounds in Hamsters, ORAL SURG. i2: 569, 1966. L 26. Glogoff. M., and others: Management of the Hemouhilic Oral Surgery J. Oral ., Y . Patient, Surg. 36: 252, 1972. 27. Reid, W. O., and others: The Use of Epsilon-Aminocaproic Acid in the Management of Dental Extractions in the Hemophiliac, Am. J. Med. Sci. 248: 184, 1964. 28. Walsh, P. N., and others: Epsilon-Aminocaproic Acid Therapy for Dental Extractions in Haemophilia and Christmas Disease: A Double Blind Controlled Trial, Br. J. Haematol. 20: 463, 1971. 29. Hall, H. D., and others: Prevention of Dry Socket With Local Application of Tetracycline, J. Oral Surg. 29: 35, 1971. 30. Khosla, V. M.: Evaluation of Three Techniques for the Management of Postextraction Third Molar Socket.s, ORAL SIJRG. 31: 189, 1971. 31. Bowie, E. J., and others: Aspirin, Platelets and Bleeding, Circulation 40: 757, 1969. 32. Schwartz, A. D., and others: Aspirin, Platelets and Bleeding, J. Pediatr. 78: 558, 1971. 33. Mequier, R. J.: Fihrinolytic Activity in Human Dental Sockets After Extraction, J. Oral Surg. 29: 321, 1971. 34. Webber, A. J., and others: Platelet Participation in Blood Coagulation Aspect,s of Nemostasis, Am. J. Pathol. 60: 19, 1970. 35. Sutor, A. H., and others: Effects of Aspirin, Sodium Salicylate and Acetominophen on Bleeding, Mayo Clin. Proc. 46: 178. 1971. 36. Yacabucci, J: E., and others: Platelet Defects of Importance in Oral Surgery, J. Oral Rurg. 30: 478, 1972. Reprint requests to : Dr. Robert L. Bump USAF School of Aerospace Medicine P. 0. Box 35302 Brooks Air Force Base, Texas 78235