Departments of Hcematology and Plastic Surgery and the University Department of Medicine, Glasgow Royal Infirmary

Transcription

1 ACUTE FAILURE OF H2EMOSTASIS DURING RESECTION FOR INTRA-ORAL CARCINOMA ; ITS TREATMENT BY AMINOCAPROIC ACID By J. F. DAVIDSON, M.B., M.R.C.P.(Ed.)., I. A. MCGREGOR, F.R.C.S., and G. P. McNICOL, M.D., Ph.D., F.R.C.P.(Ed.&Glasg). Departments of Hcematology and Plastic Surgery and the University Department of Medicine, Glasgow Royal Infirmary THIS report concerns an acute failure of the ha~mostatic mechanism which occurred during the resection of a squamous carcinoma of the lower alveolus and its successful management with the fibrinolytic inhibitor aminocaproic acid (EACA). Acute failure of this type may develop during surgery, particularly thoracic and prostatic, and during obstetrical complications, particularly abruptio placentae. It also occurs in malignant diseases, most commonly in malignancy of prostate and acute leuka~mia (Sharp, I964). In such situations aminocaproic acid has been found to be therapeutically effective in controlling the haemostatic defect (McNicol and Douglas, I964a). To appreciate the problem, however, it is necessary first to describe some of the factors concerned in the normal production and removal of fibrin. In the mammalian organism there is a constant tendency for fibrin to be deposited in the vascular tree and in the tissues. This tendency is offset by a fibrinolytic enzyme system. This proteolytic system has the ability to digest fibrin, converting it to split products which are soluble and can be removed in the circulation. According to current concepts, in normal physiological circumstances a balance is struck between coagulation and fibrinolysis, the summation of which is both an efficient mechanism of hmmostasis and a patent vascular tree. In some circumstances stimuli may occur which favour coagulation and fibrin deposition occurs ; in other circumstances, proteolysisis appropriate and there is accelerated digestion of fibrin--fibrinolysis. The fibrinolytic enzyme system (Fig. I) is the one primarily concerned in the ha:mostatic failure to be discussed and it comprises a number of components. Plasminogen Activators-----~ ~ Inhibitors Plasmin ~ - - Antiplasmins Fibrinogen), Soluble fibrin split Fibrin J products FIG. I The fibrinolytic enzyme system. Plasminogen, a /3 globulin, is normally found in plasma. Under the effect of plasminogen activator, it is converted to the proteolytic enzyme plasmin. This tendency to activation is balanced by naturally occurring inhibitors in the plasma, and it is only when the activating stimulus exceeds the capacity of these inhibitors that plasminogen conversion to plasmin occurs. Also in plasma are antiplasmins which efficiently neutralise naturally occurring free plasmin. The main effect of these antiplasmins is to 2F I77

2 178 BRITISH JOURNAL OF PLASTIC SURGERY limit the site of action of plasmin to the vicinity of plasminogen activation. This situation arises most commonly in a normal thrombus where fibrin is laid down with plasminogen. The plasminogen is activated and plasmin is produced. This plasmin though locally proteolytic in the thrombus, is neutralised by the antiplasmins as soon as it joins the main circulation and no systemic proteolysis results (Douglas and McNicol, 1964). If the stimulus to coagulation is excessive, as is found when thromboplastic substances are released into the circulation following amniotic fluid embolus for example, thrombi occur. These are completely, or partially lysed by the fibrinolytic enzyme system for activation of coagulation also activates fibrinolysis (Iatridis et a!., 1966). If the stimulus to fibrinolysis is excessive as occurs when excess amounts of plasminogen activator enter the circulation, much of the plasminogen is converted to plasmin, the inhibitory capacity of the antiplasmins is overcome and free plasmin circulates. An acute failure of the hmmostatic mechanism results from this " pathological proteolytic state ". Plasmin has wide substrate specificity, and in addition to fibrinogen and fibrin, factor VIII and other plasma proteins are degraded. Thus in hyperplasminmmia not only is fibrin digested, but also fibrinogen and factor VIII. The resulting hmmostatic defeat is consequently a complex one, but the overall effect is to cause defibrination of the blood. The defibrination syndrome is by definition a condition of hypofibrinogena:mia, which can be produced by consumption of fibrinogen in coagulation, or by digestion in fibrinolysis. In both processes, factors V, VII and VIII may either be consumed or digested. If the process is mainly thrombotic, platelets will also be reduced. Defibrination may therefore present as an acute life-threatening hmmostatic problem. The situation is further complicated by the anticoagulant properties of the fibrin split products which inhibit the action of thrombin, and also inhibit normal fibrin polymerisation. If defibrination is produced by intravascular coagulation, heparin which inhibits conversion of fibrinogen to fibrin is the treatment of choice. If pathological proteolysis is the mechanism, a proteolytic inhibitor such as aminocaproic acid or the more potent tranexamic acid, is the correct therapy. The precise cause of defibrination is often difficult to ascertain. Generally by the time studies are undertaken, the patient has hypocoaguable blood, and it is difficult without full laboratory studies to say if this has been produced by intravascular coagulation or pathological proteolysis. Case Report.--A 76-year-old male presented with an ulcer inside his mouth (Fig. 2), which had been present for six months. The clinical appearances were those of a squamous carcinoma of the right lower alveolus. There was ulceration extending along the lingual surface of the right side of the mandible from just in front of the angle to the level of the mental foramen. The mandible was clinically involved and an enlarged mobile node was palpable just below the angle of the mandible. There was no personal or family history of a bleeding diathesis. A hemiresection of mandible was undertaken with wide local clearance of tumour, and a block dissection of the neck nodes in continuity. The intra-oral defect was reconstructed using a temporal flap (McGregor, 1963). Pathological examination of the excised tissue showed the tumour to be a well differentiated squamous carcinoma with widespread infiltration of the submucosal tissue. The mandible was found to be extensively involved and of 15 lymph nodes examined by the pathologist one was largely replaced by tumour. The others showed no more than reactive hyperplasia. Towards the end of this procedure during which blood lost had been replaced by transfusion an acute generalised hmmostatic defect appeared with brisk h~emorrhage from the wound, h~emorrhage from the tracheostomy site and oozing from all venepuncture sites. Blood receplament was continued using whole blood and plasma, but un-

3 FAILURE OF H/EMOSTASIS DURING RESECTION 179 controllable hmmorrhage developed. An inspection of the wound revealed no single bleeding site. Some indication of the severity of the problem can be gauged from the fact that 12 litres of whole blood, and 2 litres of reconstituted plasma, had to be transfused to maintain a satisfactory blood volume. At one stage a recordable blood pressure could only be maintained by transfusing blood under pressure. Aminocaproic acid (5.o g.) and hydrocortisone hemisuccinate (IOO mg.) were given slowly intravenously. Within 2o minutes of the end of the injection its effect was clinically apparent. Aminocaproic acid was then continued orally in a dose of 20.0 g. daily for five days, and there were no further h0emostatic problems. FIG. 2 The squamous carcinoma of lower alveolus. It will be appreciated that in the emergency situation described a full investigation of the h~emostatic abnormality was not possible. On the basis of probability a "pathological proteolytic state" was felt to be the most likely cause, and this was supported by the preliminary coagulation investigations. On this basis the aminocaproic acid was given. INVESTIGATION OF THE H2~MOSTATIC DEFECT Materials and Methods.--Blood was taken by clean venepuncture into plastic syringes and transferred to plastic tubes. Nine parts whole blood were added to one part 3"8 per cent. sodium citrate. Blood for fibrin split product assay was clotted with tranexamic acid in a final concentration of 0.2 mg./ml. The thrombin times were performed by the method described by McNicol and Douglas (I964b). One stage prothombin times using human brain thromboplastin were by the method of Douglas (1962). The Kaolin Cephalin Clotting Time (KCCT) was performed by the method of Denson (1966), using 2 min. contact activation. The euglobulin lysis time was carried out by the method of Nilsson and Olow (1962) as modified by McNicol et al. (1965). Results are expressed in units of activity derived from a double logarithmetic plot of lysis times against activity assigning an arbitrary value of I unit to a lysis time of 3oo minutes. Normal activity is not more than 2 units. The fibrinogen assay was by the thrombin clottable protein method of Ratnoff and Menzie (1964). Normal values lie between 200 and 400 mg./ioo ml. Fibrin split

4 180 BRITISH JOURNAL OF PLASTIC SURGERY products were measured by the tanned red cell ha~magglutination inhibition immunoassay (T.R.C.H.I.I.) of Merskey et al. (1966). Normal values are below 5 ~g./ml. Plasminogen was assayed by the method of Remmert and Cohen (I949) as described by McNicol and Douglas (I064b). Normal values lie between 2 and 4 units/ml. Results.--At the time of the hmmostatic failure coagulation investigations were grossly abnormal. The thrombin time (16 seconds, control 12 seconds), the one stage prothrombin time (20 seconds, control 13 seconds) and the KCCT (lo3 seconds, control 59 seconds) were prolonged, indicating a coagulation defect almost certainly at the level of fibrinogen fibrin conversion. The plasma fibrinogen and plasminogen levels were markedly reduced and a pathological concentration of fibrin split products was present in the serum. The plasma euglobulin lysis activity was raised and the platelet count reduced (Fig. 3). ~E 200' E 100, 'E I0' -...: 300. E ~ 200' 100' E AMINOCAPROIC ACID 20-0g/24hrs. II////fJ////TJ////7////77//A PLATELET COUNT ~ _ ~, EUGLOBULIN LYSIS TIME. = A FIBRINOGEN.- = :] ~ ~ PLASMINOGEN = L ~ FIBRIN SPLIT "~25 PRODUCTS TIME [DAYS] FIG. 3 Reversion of the haemostatic defect with oral aminocaproic acid therapy. Over the next six days these abnormalities returned to normal. Indeed, the greater part of the defect had corrected within 36 hours of the introduction of aminocaproic acid therapy. DISCUSSION As has been described, towards the end of the surgical procedure, the patient developed acute h~emostatic failure. The most striking defect was hypofibrinogen~emia. The euglobulin lysis activity was much increased, reflecting abnormal amounts of plasminogen activator in the circulation, and plasminogen was depleted owing to its excessive conversion to the proteolytic enzyme plasmin. Pathological levels of fibrin split products were found on immunoassay, indicating excessive fibrin and/or fibrinogen proteolysis. These features are indicative of a "pathological proteolytic state ". The

5 FAILURE OF H/~MOSTASIS DURING RESECTION thrombocytopenia was almost certainly caused by the massive blood volume replacement with bank blood. Final confirmation of the diagnosis was obtained by the dramatic h~emostatic response to the administration of the proteolytic inhibitor aminocaproic acid. Following its introduction plasma fibrinogen and plasminogen levels rose steadily and fibrin split products fell within 36 hours to normal levels. It seems likely that the operative procedure on the tumour had released large amounts of plasminogen activator into the circulation with the subsequent conversion of plasminogen to plasmin ; hypofibrinogenmmia then resulted giving defective coagulation. At the same time digestion offibrinogen and fibrin by plasmin developed, releasing split products into the circulation which, by their antithrombin and antipolymerisation properties, were inhibitory to fibrinogen-fibrin conversion. When aminocaproic acid was given, plasminogen activator and plasmin were inhibited and the process arrested. Fibrinogen and plasminogen levels gradually rose as newly synthesised proteins were released into the circulation. The level of fibrin split products fell as those formed prior to therapy were cleared from the circulation. Following effective fibrinolytic inhibition no fresh split products were formed. With the rise in fibrinogen, and the fall in the fibrin split products which inhibit normal fibrinogen-fibrin conversion, the thrombin time and other coagulation investigations returned to normal. As the fibrinolytic stimulus did not recur, aminocaproic acid was withdrawn without ill effect. Thrombocytopenia persisted longer than would have been expected but this may have been the effect of what was more than a total exchange transfusion. Marrow examination was undertaken on the fifth post-operative day, and showed hyperplasia of all haemopoietic elements and no reduction in megakaryocytes. ISI Indications for Aminocaproic Acid Therapy.--In acute h~emostatic failure, primary emphasis in therapy should be placed on blood transfusion, fresh if possible, and it is usually also wise to give steroids (Ioo mg. hydrocortisone hemisuccinate intravenously four-hourly) to mitigate the effects of possible thrombocytopenia. If bleeding persists and there is rapid lysis of clots shortly after they form, therapy with aminocaproic acid may have strikingly beneficial effects. The usual dose of aminocaproic acid for an adult is 5"o g. intravenously over 30 minutes by infusion followed by z.o g. hourly either intravenously or orally. It must, however, be stressed that aminocaproic acid should only be given where it is specifically indicated in pathological proteolysis, and that it may be deleterious in a primary hypercoaguable state. For this reason the help of a coagulation laboratory should if possible be obtained before therapy is instituted. For a further discussion of the problem the review article of McNicol and Douglas (I967) should be consulted. SUMMARY A case is described in which a" pathological proteolytic state" developed during an extensive surgical procedure to remove a squamous carcinoma of mouth. It illustrates the acute nature of the hmmostatic emergency. H~emostatic and fibrinolytic investigations are recorded before and after aminocaproic acid therapy and illustrate the defect found in a "pathological proteolytic state" and its correction with this therapy. The pathological mechanism and the use of aminocaproic acid are discussed. We are grateful to the Medical Research Council for financial support and to Professor A. S. Douglas and Dr G. A. McDonald for their interest in this work. 2F*

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