Erosive Hemorrhagic Gastroduodenitis withFibrinolysis and Low Factor XIII

INGA MARIE NILSSON, SVEN-ERIK BERGENTZ, OLLE WIKLANDER, ULLA HEDNER

Four patients with erosive hemorrhagic gastroduodenitis werefound to have high fibrinolytic activity of the gastric juice. Noincrease in the fibrinolytic activity could be demonstrated in thecirculating blood, but the values found for fibrinogen, plasmino-gen and x2- macroglobulin were low. A high content of FDP wasfound in the serum. All patients had a markedly decreased con-tent of factor XIII. Platelet count and other coagulation compo-nents were normal. These findings were interpreted as signs oflocal fibrinolysis in the diseased parts of the gastrointestinal can-al. The bleeding stopped after oral and intravenous administra-tion of a fibrinolytic inhibitor (AMCA Cyclokapron8) and offactor XIII-containing concentrate. In bleeding from gas-troduodenal ulcer and esophageal varices, no increase in gastricfibrinolytic activity was found. It is suggested that the high localfibrinolytic activity in the stomach in erosive gastritis togetherwith the low content of factor XIII contributes substantially to thehemorrhage in this condition. These observations may lead to arevision of the treatment of such cases.

E ROSIVE HEMORRHAGIC GASTRODUODENITIS is a fairlyrare cause of gastrointestinal bleeding occurring

mainly in elderly people.Various etiological factors have been reported, such as

severe stress, trauma or surgery and drugs, such asacetylsalicylic acid, cortisone and antiphlogistics. Inmany cases no such factors are, however, demonstrable.Because of the often massive hemorrhages and the wide-spread mucosal lesions, treatment may be difficult.

This paper reports the occurrence of a high local fib-rinolytic activity in the gastric juice in association withlow factor XIII concentration in the blood in four patientswith acute erosive hemorrhagic gastroduodenitis.

From the Coagulation Laboratory, the Department ofSurgery, Malm6 General Hospital, University of Lund,

Malm6, Sweden, and the Department of Surgery,Helsingborgs Lasarett, Helsingborg, Sweden

Case ReportsCase 1. A 90-year-old man, who had always been in extremely good

health, was admitted to hospital on 18th August because of passage oflarge amounts of black stools. On admission he was pale but alert andhad no pain. The rectal content was black. Rectoscopy did not revealany source of bleeding. Four hundred ml of fresh and old blood wasaspirated from the stomach via a gastroduodenal catheter. The bleedingepisodes recurred the following two days. Laparotomy on the 21st ofAugust revealed large amounts of blood in the oral part of the smallintestine. A gastric resection according to Billroth II was performed.The gastric mucosa had normal appearance, but the duodenum was thesite of severe acute ulcerative lesions, obviously the source of bleeding.Histological examination revealed erosive duodenitis.The first two days after operation were uneventful, but an attack of

respiratory distress and signs of sepsis developed on the third post-operative day and a new episode of massive hemorrhagic on the sixth.Vasopressin was infused without significant effect on the hemorrhage.The patient developed tubular necrosis with anuria followed bypolyuria. Gastroscopy showed multiple superficial ulcerations in theremaining stomach. Based on results of coagulation and fibrinolysisstudies treatment with fibrinolytic inhibitors (AMCA) and later withfactor XIII concentrate was initiated, which controlled the bleeding.One week later massive gastric hemorrhage recurred. Bleeding wasagain almost completely controlled by the same treatment as before.Three and a half weeks after the operation the patient succumbed frombronchopneumonia and cardiac incompensation. The patient received64 units of most of which was fresh blood.Necropsy showed multiple gastric erosive lesions of the same type as

seen in the operative specimen of the duodenum. No signs of throm-bosis or embolism.Case 2. A 70-year-old woman was admitted to hospital because of

acute pancreatitis. She was treated with surgical exploration and drain-age. Five days later the patient began to bleed heavily from thestomach. Her coagulation status was examined as well as the fibrinoly-

677

Submitted for publication May 2, 1975.Supported by grants from the Swedish Medical Research Council

(B75- 19X-87- 1 1A, B75- 17X-759- IOA).

678 NILSSON AND OTHERS

TABLE 1. Results of Coagulation Studies in Cases 2, 3 and 4.

Case 2 Case 3 Case 4 Normal values

Platelet number 130,000 250,000 310,000 150,000-400,000Factor VIII (%)biol. activity 198 220 60-160immunol. 248 480 60-175P & P (%) 35 104 94 80-120Factor V (%) 95 96 106 80-120Fibrinogen (g/100 ml) 0.42 0.31 0.45 0.20-0.40Antithrombin III (%) 50 72 84 60-140Plasminogen (%) 35 60 35 60-140oc2M (%) 74 49 80-120FDP (pg/ml) 32 15 38 0-10Ethanol gelation test neg neg neg negFactor XIII (units) 6 9 9 11-31Gastric juiceFibrinolytic activity(lysed area in mm2)unheated plates 1254 1200 0heated plates 1080 730 0FDP (lAg/ml) 45 115 6000 0

tic activity of the gastric juice (Table 1). The bleeding was controlled byoral treatment with AMCA. This treatment was continued until thepatient died from pancreatitis three days later without recurrence of thebleeding. Necropsy revealed erosive gastritis.Case 3. A 77-year-old woman had a previous history of car-

diosclerosis and arthrosis, for which she had been treated with in-domethacin and cortisone. She was admitted with an acute severegastrointestinal hemorrhage with hematemesis, severe tachycardia andlow blood pressure. Gastroscopy 12 hours after admission showedmultiple, bleeding erosive lesions in the stomach. Biopsy confirmed thesuspicion of acute erosive and hemorrhagic gastritis. Coagulationstudies were performed (Table 1). Based on these the patient was givenAMCA orally and factor XIII-concentrate, which immediately control-led the bleeding. No further bleeding occurred, and the patient could bedischarged after 10 days.Case 4. A 60-year-old woman, previous to admission, had been

healthy with the exception of a duodenal ulcer 24 years ago. She wasadmitted with a one day history of gastrointestinal hemorrhage withhematemesis and melena. During the first three days in hospital she waswell, but then massive hemorrhage recurred. Laparatomy was per-formed. A small duodenal ulcer was found, as well as multiple hemor-rhagic erosive lesions in the gastric mucosa. Pyloroplasty and vagotomywas done. The following day the patient started to bleed again. Gastricresection according to Billroth II was done. In the gastric mucosamultiple superficial ulcerations were found and the diagnosis erosivehemorrhagic gastritis could be confirmed histologically. Ten days latermassive bleeding occurred. She was at that time considered inoperable.Coagulation studies were carried out (Table 1). Following oral treat-ment with AMCA the bleeding promptly stopped. The patient reco-vered slowly and was discharged one month later.

Methods

Platelet and coagulation studies. Platelet count, Ivybleeding time, coagulation time, activated partial throm-boplastin time (APTT), one-stage prothrombin time, fac-tor V, prothrombin + factor VII + factor X (Owren's P &P-test), factor VIII (AHF) (biologic activity) and fibrino-gen were determined with methods described earlier.27'28Factor VIII was also determined immunologically ac-cording to Holmberg and Nilsson.19 Antithrombin III was

determined immunochemically by the rocket method ofLaurell.15 The thrombin time and Reptilase time wereperformed as described by Latallo et al.21 The ethanolgelatin test was used for determining fibrin monomersaccording to Godal et al.12 Factor XIII (FSF) was mea-sured by a slight modification18 of the dansylcadaverinemethod of Lorand et al.23 Normal range 11-31 FSFunits/ml.

Fibrinolytic studies. Thefibrinolytic activity of plasmaand resuspended euglobulin precipitate was measured onunheated bovine fibrin plates, as described by Nilssonand Olow.28'29 The pH of the gastric juice was first ad-justed to 7.0 and the activity measured on both unheatedand heated fibrin plates. Plasminogen was measured byan immunochemical method.9 Fibrinifibrinogen degrada-tion products (FDP) were determined with the im-munochemical method of Nilehn14.25 in gastric juice andin serum samples obtained from blood collected withEACA and thrombin. In some samples the FDP weretyped in the way described by Bouma et al.4 2- macrog-lobulin (oc2M) was determined as previously described.16The concentration ofAMCA in serum was determined bya clot lysis method described by Nilsson, Sjoerdsma andWaldenstrom.30 For determination of AMCA in urine amethod described by Andersson et al.' was used. It isbased on high voltage paper electrophoresis and photo-metric determinations of the ninhydrin complex.

MaterialFraction I-0. This fraction is prepared by AB Kabi,

Stockholm (AHF Kabi) according to the glycerinemethod of Blomback and Blomback.3 It contains not onlyfactor VIII and fibrinogen, but also factor XIII. Thefactor XIII content of one bottle (100 ml) correspondsapproximately to that of 250 ml of plasma. AMCA.

Ann. Surg. * December 1975

HEMORRHAGIC DUODENITIS

Aminomethyl-cyclo-hexane-carbonic acid (Cyclokap-rona, AB Kabi) for intravenous and oral administration.Plasmin. Human plasmin (Kabi DTC 48; Grade A, ABKabi, Stockholm). EACA. EACA solution from ABKabi, containing 0.1 g EACA/ml. Trypsin. (Trypure, ABNovo), Dissolved in 0.9% NaCl. Aprotinin (Trasylolg,Bayer). Solution containing 10,000 KIE/ml. Further dilu-tions with 0.9% NaCl. Pepsin. (B.D.H. LaboratoryChemical Division). Dissolved in 0.9o NaCl.

Results of Coagulation Analyses

Case 1. The results of the coagulation analyses andsome other relevant data in Case 1 are given in Fig. 1.At the first examination (Aug. 19th, 1974) the platelet

count and the values found for P & P, factor V, anti-thrombin III, thrombin time, plasminogen and OC2M werenormal. The fibrinogen level was 0.25 g/100 ml. The fac-tor VIII level was normal when determined with a biolog-ical method, but raised when assessed with an im-munological procedure. The FDP level in serum was low(7.5 ,g/ml). No fibrinolytic activity could be de-monstrated in the circulation. The factor XIII content (13FSF units) was in the lower part of the normal range. Theethanol gelation test was negative.Two days after gastrectomy the coagulation system

was found to be impaired. Analyses performed on August22nd and 23rd thus showed a low platelet count. Thefibrinogen level had not risen after the operation. Thevalues found for antithrombin III, c2M and plasminogenhad decreased, and the amount of FDP (25 pg/ml) in theserum had increased. The thrombin time and the Re-ptilase time were normal. The ethanol gelatin test waspossibly positive. These findings suggested that the pa-tient had proteolysis with activation of the coagulation aswell as of the fibrinolytic system.The patient was given heparin and AMCA on August

23rd to 26th, during which the platelet count increasedcontinuously. Also the values found for fibrinogen, plas-minogen and oc2M increased.

Examination of the coagulation system on August 26thto 28th in association with massive gastric hemorrhageindicated an activation of the fibrinolytic system. Theplatelet count was normal or slightly decreased. P & Pwas somewhat low, but promptly rose after administra-tion of Vitamin K. The factor V level was normal. TheAHF levels, especially when determined with the im-munochemicai method, were high. The fibrinogen fellsubstantially to 0.19 g/100 ml and the plasminogen to20%. Antithrombin III did not fall further. oc2M was aslow as 25%. The patient had FDP in the serum. The FDPwere of low molecular weight type, i.e. D- andE-products. Factor XIII was low, 9 FSF units. Examina-tion of the blood on fibrin plates showed no fibrinolyticactivity. The ethanol gelatin test was negative.

679The gastric juice showed high fibrinolytic activity on

both unheated and heated fibrin plates (Table 2). Theactivity was slightly lower on heated plates. Addition ofEACA (10 mg/ml) to the gastric juice reduced the activityby about 80%. The plasmin level of the gastric juice wasdetermined with Laurell's rocket method.'4 The activityof the gastric juice corresponded to that of about 5 CTAunits of plasmin. The juice also contained a substantialamount of FDP (D + E products). The fibrinolytic activ-ity was neutralized by administration ofAMCA locally inthe stomach.

Intense intravenous and later oral therapy with AMCAwas started on August 29 with simultaneous control ofthe concentration of AMCA in the serum and urine.Maintenance of the serum AMCA at a level between4-10 pg/ml required AMCA in a dose of 6-10 g a day. Thepatient had polyuria and excreted 50-90% of the AMCAin the urine.

Factor XIII was repeatedly found to be low (Fig. 1). OnAugust 31st and September 1st the patient was givenfactor XIII (fraction 1-0) in a dose corresponding to thatin 2,000 ml of normal plasma.

During treatment with AMCA and factor XIII concen-trate the fibrinogen content rose to levels above 0.50g/100 ml. oc2M increased and FDP in the serum fell sub-stantially. P & P and factor V persisted unchanged, andantithrombin III did not decrease. Factor XIII rose tonormal level.

For irrelevant reasons the patient was given AMCAonly sporadically between September 6th-8th. On Sep-tember 8th he again showed signs of fibrinolysis and bledcopiously. The fibrinogen content fell to 0.36 g/100 ml.The FDP in the serum rose to 35 ig/ml and the xM fell.The fibrinolytic activity of the gastric juice was high. Theplatelet count, P & P and factor V remained normal. Theethanol gelation test was negative. The factor XIII con-tent decreased to 5 FSF units/ml.

TABLE 2. Studies on Gastric Juice From Case 1.

Unheated Heatedplates plates FDP Plasmin

Date Gastric juice mm2 mm2 pg/ml CTA units/ml31/8 812 500 1000 5

(D +E)31/8 Addition of 10 mg 210

EACA per ml gastricjuice

1/9 After administra- 75 0 0 0tion of AMCA locallyin the stomach

1/9 8 hours after AMCA 960 400 0 5locally

3/9 820 360 800 2(D +E)

9/9 361 3560(D +E)

11/9 890 81014/9 1311

VOl. 182 * NO. 6

NILSSON AND OTHERS Ann. Surg. * December 1975

3 FIG. 1. Pertinent data on% Pi./mmU1~ laboratory findings, thera-

PLATELETS 500 200000py and course in Case 1.

per mm .--I.AHF ACT. 100 1600

300 120000

AIHF IMM.

100 40000

AMCA vU

g9 24 hrs. | 6 6 6

AMCA : o

g 12. hrs.

HEPARIN mg i.v./24hrs _ m9g N I-oI-O o-o i-a o-OFRACTION 1-0 (f3M.lUibrI 150w

- 00mi. s0oIBLOOD TRANSF t:l unit Mflh tT I t t I tMt inlr t T TtT1TZT I

Ai FICMc~SPIft.

BLEEDING G~~~~~~ASTPIC PULM4OMRY GASTRIC SLBLEEDING L;iL CHAmNES Li. Li

CIRCNSUFF

DATEE920A21 I

- POLYURtA -IA POLYURIADATE 9 20 22 21. 26 28 30 1 3 5 7 9 11 13 15

i9 ~~~~~~~~sept.

From September 10th the patient received AMCA by ethanol gelation test was positive. The platelet countmouth at short intervals (Fig. 1) and factor XIII concen- remained normal as did P & P and factor V. Throughouttrate daily. The fibrinogen values rose to high levels. The the disease the patient had a high level of AHF relatedfactor XIII content became normal. On one occasion the protein. The thrombin and Reptilase times were normal

680

HEMORRHAGIC DUODENITIS

throughout, except for prolongation of the thrombin timeduring treatment with heparin. The fibrinolytic activity ofthe blood was not increased.Cases 2, 3 and 4. The results of the coagulation

analyses on the 3 other cases with erosive gastritis aregiven in Table 1. In these patients the platelet count, P &P and factor V were normal. The factor VIII relatedantigen was high. The plasminogen, xoM and factor XIIIwere decreased, and the FDP in the circulation was in-creased. The gastric juice showed increased fibrinolyticactivity particularly on unheated fibrin plates.

Examination of Gastric Juice From Non-bleeding Pa-tients.

Gastric juice obtained from 15 patients (referred for thepentagastrin test) without gastric hemorrhage wereexamined. The samples exhibited little or no fibrinolyticactivity on fibrin plates.

Gastric juice from patients with upper intestinal tractbleeding due to other causes was examined. Four pa-tients with massive hemorrhage from a verified gastric orduodenal ulcer were studied with regard to their fib-rinolytic activity in the gastric juice. Three of them hadno activity at all, and one had a very slight activitycompared with the patients with erosive gastritis. FactorXIII was not decrea!;ed in any of these patients.To differentiate the plasmin activity in the gastric juice

in the patients with erosive gastritis from that of othergastric enzymes with proteolytic activity the effect ofplasmin (9.4 and 4.7 CTA units/ml), trypsin (100 and 10pg/ml) and pepsin (10-400 ig/ml) on unheated and heatedfibrin plates was determined with and without EACA (0.1and 10 mg/ml) and with and without Trasylol® (1, 10 and100 KIE/ml). Pepsin showed no fibrinolytic activity onfibrin plates at pH 7. Plasmin exhibited three times asmuch activity on unheated plates, as on heated plates.Trypsin showed activity, which was roughly equal onheated and unheated plates. EACA in the doses usedsuppressed the effect of plasmin by about 50%, but hadno demonstrable effect on the activity of trypsin. Trasylolinhibited both trypsin and plasmin, the inhibition varyingwith the dose given.

DiscussionMost human tissues contain fibrinolytic activators,2

mainly in the small vessels.3' The fibrinolytic activity ofthe gastric mucosa has received relatively little attention.A plasmin-like activity was however, found by Cox et al.in the gastric veins in patients with gastric haemorrhage.The plasmin-like enzyme in blood from the gastric vein insuch patients has recently been identified as plasmin.32Disseminated intravascular coagulation has been

claimed to be of pathogenetic significance for developingerosive gastritis.24"3 This could not be confirmed in the

681

present study. The first case showed signs of activationof the coagulation process but only in the early post-operative course. This patient developed a peripheralcirculatory collapse in combination with throm-bocytopenia and positive ethanol gelation test indicatingthe presence of fibrin monomers in the circulation whichis claimed to be typical for DIC.26 Heparin also producedsome improvement in the patient's coagulation status.During the further course the laboratory findingssuggested an activation of the fibrinolytic system ratherthan of the coagulation system. The patient thus had anormal platelet count, negative ethanol gelation test,normal P & P and factor V and high factor VIII, but thevalues for fibrinogen, plasminogen and o2M were low. Itis well known that oc2M can bind both plasmin and throm-bin'" and thus fall when the coagulation system or thefibrinolytic system is activated. Antithrombin III wasnormal. The patient had a high content of FDP in serumwhich decreased during adequate AMCA-treatment. Noincrease in the fibrinolytic activity could be demonstratedin the circulating blood. The fibrinolytic activity of thegastric juice was, however, high. This activity was due toa plasmin-like enzyme and not to other gastric proteolyticenzymes. We interpret these findings in the blood andgastric juice as compatible with the presence of localfibrinolysis in the stomach and duodenum but without ageneralized fibrinolysis. On passage of the blood throughthe stomach and duodenal wall activators are released tothe blood and the plasminogen is transformed, at leastlocally, to plasmin, which breaks down fibrinogen andfibrin. The activators and the plasmin are neutralized byinhibitors, such as xc2M, in the general circulation andtherefore no activity can be measured in the circulation.This is in good agreement with the findings6' 32 of plasmin-like enzyme in the gastric vein but not in the gastricartery or peripheral veins. In such cases plasminogenactivators and/or plasmin must also enter the gastricjuice, causing dissolution of the hemostatic thrombiwhich successively form in the eroded areas of theduodenum and stomach. In this way the local activationof the fibrinolytic system contributes to a continuation ofthe hemorrhage. The effect of administration of AMCA

It is of interest to note that the factor XIII content waslow in all four patients. Hedner et al.'7 measured factorXIII with the specific dansylcadaverine method ofLorand et al.23 in patients with various diseases. Theyfound low levels in patients with sepsis and other condi-tions associated with abnormal proteolytic activity (fib-rinolysis and/or activation of the coagulation system). Nocorrelation was found between the factor XIII and thefibrinogen values or the levels of FDP which suggestedsome specific degradation of factor XIII unrelated to thefibrinogen degradation. Egbring et al.8 produced evi-dence that factor XIII can be degraded by proteases in

Vol. 182 - No. 6

682 NILSSON A

the leukocytes. It is not known why the factor XIII levelis low in erosive gastritis, but the mechanism responsibleis probably the same as that in other cases of abnormalproteolysis. The rapid decline in factor XIII seen in case1 in connection with the bleeding episodes is noteworthyand supports this assumption.

Factor XIII is necessary to stabilize the fibrin struc-ture. A non-stabilized fibrin clot is more readily dissolvedby urokinase activated plasminogen than a stabilizedone.10'22 The low factor XIII levels in our patients witherosive gastritis must thus render the clots formed in thestomach more susceptible to the local fibrinolytic activitywith aggravation of the bleeding as a result. In our firstpatient and in one of the others (case 3) infusion of factorXIII containing fraction 1-0 together with administrationof AMCA, also seemed to be of benefit. The AHF leveland especially AHF protein were markedly increased inthese patients. A high AHF level is a sensitive sign ofabnormal tissue destruction.20 No side effects to thetreatment with AMCA were observed. No patient de-veloped thrombus.

In those patients with erosive gastritis and duodenitis,then, the local fibrinolytic activity in the stomach washigh and the factor XIII content low, while similar ab-normalities were not found in patients with gas-troduodenal haemorrhage due to an ulcer. There isreason to assume that these disturbances contributedsubstantially to the markedly increased bleeding ten-dency. These observations may lead to a revision of thetreatment of such cases. If it is known from the verybeginning that the patient has an erosive gastroduodenitiswith high fibrinolytic activity in the stomach he shouldreceive adequate antifibrinolytic treatment both i.v. andby mouth and also be treated with factor XIII. Suchmeasures might make operation unnecessary, which is ofparticular importance in these elderly patients with dif-fuse erosive lesions in the stomach and duodenum.

References1. Andersson, L., Nilsson, I. M., Colleen, S., et al.: Role of

Urokinase and Tissue Activator in Sustaining Bleeding and theManagement Thereof with EACA and AMCA. Ann. N.Y. Acad.Sci., 146:642, 1968.

2. Astrup, T.: Tissue Activators of Plasminogen. Fed. Proc., 25:42,1966.

3. Blomback, B. and Blomback, M.: Purification of Human andBovine Fibrinogen. Arkiv. Kemi, 10:415, 1956.

4. Bouma, B. N., Hedner, U. and Nilsson, I. M.: Typing of Fibrino-gen Degradation Products in Urine in Various Clinical Disorders.Scand. J. Clin. Lab. Invest., 27:331, 1971.

5. Cormack, F., Jouhar, A. J., Chakrabarti, R. R. and Fearnley, G.R.: Tranexamic Acid in Upper Gastrointestinal Haemorrhage.Lancet, I: 1207, 1973.

6. Cox, H. T., Poller, L. and Thomson, J. M.: Gastric Fibrinolysis. APossible Aetiological Link with Peptic Ulcer. Lancet, I: 1300,1967.

7. Cox, H. T., Poller, L. and Thomson, J. M.: Evidence for the

Release of Gastric Fibrinolytic Activity into Peripheral Blood.Gut, 10:404, 1969.

8. Egbring, R., Schmidt, W. and Havemann, K.: Possible Destructionof Factor I and XIII by Leucocyte Proteases in AcuteLeukaemia. IVth Int. Congr. Thromb. and Haemostasis, Vienna,June l9th-22nd, 1973.

9. Ekelund, H., Hedner, U. and Nilsson, I. M.: Fibrinolysis in New-borns. Acta Paediatr. Scand., 59:33, 1970.

10. Feddersen, C. and Gormsen, J.: Plasmin Digestion of Stabilizedand Nonstabilized Fibrin. Illustrated by Immunoelectrophoresisand Haemagglutination Inhibition Immuno Assays. Scand. J.Haematol., 8:461, 1971.

1 1. Ganrot, P. 0. and Nilehn, J.-E.: Competition Between Plasmin andThrombin for oc2-Macroglobulin. Clin. Chim. Acta, 17:511, 1967.

12. Godal, H. C., Abildgaard, U. and Kierulf, P.: Ethanol Gelation andFibrin Monomers in Plasma. Scand. J. Haematol., Suppl. 13:189,1971.

13. Hardaway, R. M.: Syndromes of disseminated intravascular coagu-lation. Springfield, Charles C. Thomas, 1966.

14. Hedner, U. and Nilsson, I. M.: Urokinase Inhibitors in Serum in aClinical Series. Acta Med. Scand., 189:185, 1971.

15. Hedner, U. and Nilsson, I. M.: Antithrombin III in a ClinicalMaterial. Thromb. Res., 3:631, 1973.

16. Hedner, U., Nilsson, I. M. and Jacobsen, C. D.: Demonstration ofLow Content of Fibrinolytic Inhibitors in Individuals with HighFibrinolytic Capacity. Scand. J. Clin. Lab. Invest., 25:329, 1970.

17. Hedner, U., Henriksson, P. and Nilsson, I. M.: Factor XIII in aClinical Material. Scand. J. Haematol., 1975.

18. Henriksson, P., Hedner, U., Nilsson, I. M., et al.: Fibrin-stabilizing Factor (factor XIII) in the Fetus and the NewbornInfants. Pediatr. Res., 8:789, 1974.

19. Holmberg, L. and Nilsson, I. M.: Studies on Two Genetic Variantsof von Willebrand's Disease. N. Engl. J. Med. 288:595, 1973.

20. Holmberg, L. and Nilsson, I. M.: AHF Related Protein in ClinicalPraxis. Scand. J. Haematol., 12:221, 1974.

21. Latallo, Z S., Wegrzynowicz, Z., Budzynski, A. Z. and Kopec, M.:Effect of Protamine Sulphate on the Solubility of Fibrinogen, ItsDerivatives and Other Plasma Proteins. Scand. J. Haematol.,Suppl. 13:151, 1971.

22. Lorand, L. and Jacobsen, A.: Accelerated Lysis of Blood Clots.Nature, 195:911, 1962.

23. Lorand, K., Urayama, T., de Kiewiet, J.W.C. and Nossel, H. L.:Diagnostic and Genetic Studies on Fibrin-stabilizing Factor witha New Assay Based on Amine Incorporation. J. Clin. Invest.,48:1054, 1969.

24. McKay, D. G.: Disseminated Intravascular Coagulation. An Inter-mediary Mechanism of Disease, Hoeber Medical Division, NewYork, Harper and Row, London, Everton, 1965.

25. Nilehn, J.-E.: Separation and Estimation of "Split Products" ofFibrinogen and Fibrin in Human Serum. Thromb. Diath.Haemorrh., 18:487, 1967.

26. Nilsson, I. M.: Haemorrhagic and Thrombotic Diseases. London,John Wiley and Sons, 1974.

27. Nilsson, I. M., Blomback, M. and Ramgren, O.: Haemophilia inSweden. I. Coagulation Studies. Acta Med. Scand., 170:665,1961.

28. Nilsson, I. M. and Olow, B.: Determination of Fibrinogen andFibrinogenolytic Activity. Thromb. Diath. Haemorrh., 8:297,1962.

29. Nilsson, I. M. and Olow, B.: Fibrinolysis Induced by Streptokinasein Man. Acta Chir. Scand., 123:247, 1962.

30. Nilsson, I. M., Sjoerdsma, A. and Waldenstrom, J.: Antifibrinoly-tic Activity and Metabolism of E-aminocaproic Acid in Man.Lancet, 1:1322, 1960.

31. Pandolfi, M., Isacson, S. and Nilsson, I. M.: Low FibrinolyticActivity in the Walls of Veins in Patients with Thrombosis. ActaMed. Scand., 186:1, 1969.

32. Thomson, J. M.: Fibrinolysis and the Stomach: Biochemical Iden-tification of the "Plasmin-like" Enzyme. Thromb. Diath.Haemorrh., 31:291, 1974.

kND OTHERS Ann. Surg. * December 1975