THROMBOSIS
Vol.
RESEARCH
Printed
in Great
11, PP. 643-651, 1977 Pergamon
Britain
Press,
Ltd.
FACTOR VIII INBIBITOR BY-PASSING ACTIVITY (FEIBA) IN THE MANAGEMENT OF PATIENTS WITH FACTOR VIII INHIBITORS F.E. Preston*, *University Sheffield
R.C.W. Dinsdale**, P.J. Wyld* and
D.J. Sutcliffe*, J.F. Hamlyn**
G. Bardhan*,
Department of Haematology, The Royal Infirmary, ~6 3DA and **The Charles Clifford Dental Hospital, Sheffield SlO 2SZ England
(Received
14.7.1977; in revised form 1.9.1977. Accepted by Editor A.L. Bloom)
ABSTRACT Three patients with high titre factor VIII inhibitors have been treated with factor VIII inhibitor by-pass Successful management of sponactivity (FEIBM. taneous bleeding episodes was achieved in all three In one patient dental surgery was performed patients. three tips without haemotrhagic complications and on each occasion tbs only treatment given was FEIBA and The only complication of an antifibrinolytic agent. FEIBA has been a significant increase in the factor VIII inhibitor concentration of one patient. Disseminated intravascular coagulation did not occur*
INTRODUCTION
Factor VIII inhibitors occur in 6 - 8% of haemophiliacs. They may also occur spontaneously in the elderly or in patients with auto-immune or collagen disorders (1). Rs9ardless of ths underlying pathology the management of the haemorrhagic manifestations of patients with factor VIII inhibitors is notoriously difficult. Until recently the most satisfactory method of treating these patients was by attempting to neutralise the inhibitor with large amounts of factor VIII concentrate but even this is not always successful. Recently there have been a number of reports suggesting that prothrombin complex concentrates may be a useful alternative method of tnsating these patients (2,3). %ae we present details of our experience with factor VIII by-pass activity (FEIBA).
643
644
FEIBA ANB FACTOR VIII. INHIBITOR
Vol.ll,No.5
PATIENTS Patient 1 G.K., an 81 year old lady, had been perfectly well until June 1975, when she developed very severe bruising after a minor fall. During the next 14 months she complained of repeated and extensive spontaneous bruising which was of sufficient severity to warrant blood transfusion. During this period she also had a proven spontaneous haemarthrosis of the left knee. In August 1976 she was transferred to the Royal Infirmary, Sheffield, with a four week history of a gradually increasing spontaneous haematoma of the right breast. On admission her haemoglobin was 6.6 g/dl. The diagnosis of acquired haemophilia was established on the basis of F.VIII C 2%, F.VIII R.A. 105% and a factor VIII inhibitor 1080 u/ml. There were no abnormalities of any other clotting factor and platelet count and functions were both normal. There was no clinical or laboratory evidence of autoimmune disease. The anaemia was corrected by blood transfusion and she was observed for 48 hours. At this tims a painful and rapidly progressive spontaneous haematoma developed in the flexor aspect of the right forearm. This was associated with tingling and parasthesia of the fingers of the right hand. It was decided to give FEIBA 40 units/kg intravenously. Within four hours the pain had subsided and there was no further progression of the haematoma. The FEIBA was administered at the same dosage at eight-hourly intervals. The parasthesiae ceased 12 hours later. After five days the FEI8A was discontinued and two days later G.K's haemoglobin again began to fall and this coincided with a spontaneous haematoma of the left forearm. FEIBA was again administered at the same dosage as previously and again there was rapid clinical response. Patient 2 A.D., a 74 year old lady, was transferred to the Royal Infirmary, Sheffield, with a ten week history of recurrent sponShe gave a 14 year history of taneous bruising and epistaxis. rheumatoid arthritis for which she was receiving enteric-coated prenisolone, 5 mgm bd., ibuprofen, dextropropoWphens hydra- ’ A diagnosis of acquired haemophilia chloride and paracetamol. was established on the basis of F-VIII C 1.5%, F.VIII R-A. 11096 There were no abnormalities and factor VIII inhibitor 250 u/ml. of any other clotting factor, and platelet count and function On admission her haemoglobin was 7.5 g/alwere both normal. She was observed for approximately 10 days, during which time she required two blood transfusions for rapidly developing anaemia. During this period there was no haematological evidence of haemolysis and since.faecal occult blood were very strongly positive, it was considered that the rapidly developing anaemia Radiological investiwas due to gastrointestinal haemorrhage. gation of the gut failed to reveal the cause of the haemorrhage. After the second blood transfusion she was commenced on FEIBA, 40 units/Kg 8-hourly and this was continued for a period of ten As can be seen from Fig. 1, there was no further fall in days. At the end of the treatment her haemoglobin during this period. period the FEIBA was discontinued and she was commenced on During the following two weeks her immunosuppressive therapy.
645
FEIBA AND FACTOR VIII INHIBITOR
Vol.ll,No.5
general condition remained satisfactoryand‘& was eventually transferredback to the referring hospital. It was learned that she died two months later from massive gastrointestinal haemorrhage. An autopsy was not performed. E E.I.6.A 15, l4,
6_ 5,
,,,,,,,,,1,III,,11111111 15 17 19 21 23 25 27
29
1
3
5
7
8
OCt FIG. 1 The influence of FEIBA on the haemoglobin of a patient with gastrointestinalhwmrrhage associatedwith acquired haemophilia
Patient 3 G.P. is a known severely affected haemophiliac (F.VIII C < 1%) with a factor VIII inhibitor level of 12 u/ml. During 1976 he was frequently incapacitatedby recurrent spontaneoushaemarthroses and it was therefore decided to tnat all future joint bleeds with FEIBA. During the following sevenmonth period he received 24 treatments. Initially the dose of FEIBA was 14 units/kg, but satisfactoryclinical responses ware subsequentlyobtained with 7 units/kg. The results of this form of therapy appeared to be very encouraging in that there was rapid relief from pain and on no occasion did the haemarthrosis progress* G.P. himself was convinced that the joint bleeds were arrested by the treatment. In October 1976 he was seen by a dental surgeon on account of severe toothache. Total dental clearance was recommended and in view of the patient's previous responses to FEIBA, it was decided to use this product to cover the extractions. On the first occasion an upper second premolar was extracted using local anaestheticpmcmkd by intravenousFEIBA, 30 units/kg, and epsilon aminocaproicacid (EACA) 0.1 g/kilo. There was no imnsdiah or delayed haemorrhage. Oral EACA was continued, 6 g six-hourlyuntil the sutures were removed. Oral antibiotics WHZJ the only other drugs given during this period.
646
FEIBA AND FACTOR VIII INHIBITOR
Vol.ll,No.5
Six weeks later a first and second premolar and a second molar were extracted under FEIBA cover. EACA and antibiotics were administered as before. Intravenous FEIBA 60 units/kg was given immediately before the extractions which were performed under local anaesthetic. Eaemostasis was considered so satisfactory that it was decided to continue and an additional first molar was also extracted. This prolonged the operation by forty minutes since the tooth had large roots and the extraction was technically difficult. The post-operative period was uneventful apart from some slight oozing which occurred from a suture hole 24 hours after the extraction This was readily controlled by local measures and a further injection of FEIBA, 30 units/kg. Dental surgery was again undertaken three months later. This was performed under local anaesthetic preceded by intravenous FEIBA, 60 units/kg and EACA 0.1 g/kg. On this occasion five teeth were extracted - an upper right first and second premolar, first and second molars and an upper left first premolar. Both upper first premolars had three roots and a transalveolar approach was necessary on the left side, requiring incision and mucoperlosteal flap with suturing. There was no bleeding from this area post-operatively. On the right side there was some oozing from the soft tissues of the molar sockets which were the site of active periodontal disease with One further injection of FEIBA, 30 units/kg was hyperaemia. given twelve hours later and oral antibiotics were administered On this occasion oral antlfibrinolytic treatment as before. The was continued with tranexamic acid, 0.5 g six-hourly. post-operative course was uneventful and wound-healing was normal. ’ METHODS Basic haematological investigations, including tests of coagulation were performed as described by Dacie and Lewis (4). Plt?lz fibrinogen was quantitated by the Ellis Stranslcy (5) . Serum F.D.P's were measured by the Burroughs Wellcom F.D.P. kit. Plasma anti-thrombln III was measured by a radial Factor VIII antibodies were immunodiffusion technique (6). An assayed by the method described by Rizza and Biggs (7). antibody unit is defined as the amount of antibody which destroys 0.5 units of factor VIII after four hours incubation. Whenever possible, blood samples were taken before the administration of FEIBA and at 15 minutes, 60 minutes and 120 At each sampling the following tests were minutes post-FEIBA. performed : whole blood clotting tima (WBCT): thrombin clotting time: prothrombln time; kaolin-cephalln clotting tine: serum F.D.P's: plasma fibrinogen: anti-thrombin III and platelet count. Responses were assessed on seven separate occasions in patient G.P. and on three occasions in each of the The concentration of FEIBA varied from 13 other two patients. units/kg to 60 units/kg.
Vol.ll,No.5
FEXBA AND FACTOR VIII INBIBITOR
647
LABORATORY RESULTS At all FEIBA concentrationsgreater than 13 Units/kg of the whole blood clotting time significantimprovenuant occurred.fifteenminutes after infusion (Table 1). Generally, t& degree of correction related to the concentrationof the infused material but on no occasion was the WBCT completely normalised. At two hours some degree of correction of the WBCT was still evident. The kaolin-cephalinclotting time was also shortenedby FEIBA, but although the observed effect was proportioned to the concentrationof infused FEISA, it was usually less than the correspondingchange in the WBCT. WhenFEIBAwas mixed with the patient's plasma in the laboratorythere was significant shorteningof the KCCT and this was always greater than the correspondingin viva effect (Table 2). TABLE 1 Chahges in Whole Blood Clotting Time OJBCT) following FEIBA Infusion (PatientG.P.)
Pre Infusion (mins.) 13 13 13 20 30 30 60
33 24 24 30 22 36 35
WBCT Post Infusion (mins.) 29 22 22 15 16 21 13
%
Reduction
12 8 8 50 27 42 63
The prothrombin time was also shortened one or two seconds by FEIEA administration. There was no evidence of disseminated intravascularcoagulation in any of the 13 studies. In particular, platelet counts, plasma fibrinogen, anti-thranbinIII and serum F.D.P. remained unchanged for the period of investigation. &&$&&&&In!! of FEIBA The only c lication detected was a marked incre;yh;; the factor VIII % in bitor of patient G.P. (Fig. 2). patient no chenge occurred in the factor VIII inhibitor level during the first thnee months of treatment by FEIBA. f)uring this period 11 treatmentswere given, in most instances the
648
FEIBA AND FACTOR VIII INBIBITOR
Vol.ll,No.5
TABLE 2 Comparison of In Vitro and In Viva Effects of FEIBA on the KCCT
Patients
(sees. )
G.P.
G.K.
A.D.
195
120
190
KCCT (sacs.) 15 Post FEIBA infusion*
152
117
164
KCCT (sets.) Mixing Experiment Patient's plasma + FEIBA (1 unit/ml)
83
80
79
KCCT
*Dose 1 unit/ml plasma calculated on basis of blood volume 7QrWkg Following the first dental extraction dose being 7 units/kg. the inhibitor rose from 14 to 20 units/ml, but two months later it had receded to 12 units/ml. The second dental procedure was accompanied by a marked rise in the inhibitor to 48 units/ml. At no time has this patient received any other blood product.
Dental Extraction
Dental Extraction
50, 40 I Factor VIII Inhibitor (u/knl) 30, 20, 10 , JASONDJ 1976
1977
Fig. 2 Factor VIII inhibitor levels in patient GOP-
Vol.ll,No.5
FEIBA AND FACTOR VIII INHIBITOR
649
DISCUSSION
The treatment of patients with factor VIII inhibitors Recent reports on the use of is notoriously difficult. prothrombin complex concentrates and factor VIII by-passing fractions in the management of these patients is therefore of However, experience in their use considerable interest. remains limited and not all workers are convinced of the It is not always easy to efficacy of these products (3,8,9). Sponassess the therapeutic value of haemostatic agents. taneous cessation of bleeding in a haemophiliac is a recognized phenomenon and clinical evaluation of a concealed haemorrhage Thus the clinical responses of the is usually subjective. patients G.K. and A.D. may have been entirely fortuitous, although rapid regression of neurological symptoms in an inadeThe assessment of quately treated haemophiliac is unusual. post dental extraction haemorrhage thus offers considerable advantages since the bleeding site can be directly observed. Dental surgery is an effective haemostatic challenge and the absence of post extraction haemorrhage in a severely affected haemophiliac who has not received factor VIII cover is a rare The absence of bleeding in patient G.P. thus provides event. good evidence of the therapeutic efficacy of FEIBA, particularly since the unusual root formation of his molar and premolar teeth made the second and third operations extremely It may be argued that the antidifficult and time-consuming. fibrinolytic drugs were primarily responsible for maintaining Although this is a adequate haemostasis in this patient. possibility we believe that it is highly unlikely, particularly during the sacond and third operative sessions when substantial surgical manipulations were required. The reports of thromboses which have occurred in patients concentrate replacement therapy (10,11,12) receiving factor should temper enthusiasm for this form of treatment with considerable caution and evidence for unwanted activation of the In the coagulation mechanism should be carefully sought. ;zsts described here, FEIBA was administered at doses ranging - 60 u/kg. At these concentrations there was no clinical or laboratory evidence for intravascular coagulation. The mechanism by which FEIBA functions is unknown, although there is experimental evidence to show that it is not due to thrombin or the activated clotting factors Ix and x (13). resent state of knowledge it is difficult to monitor In the FEIBA tK erapy since the coagulation responses are somewhat unpredictable. In all instances the administration of FEIBA produced shortening of the activated partial thromboplastin time iFXJ$, the prothrombin time and the whole blood clotting time . The shortening of the APTT was always less than that observed when the patient's plasma was mixed with FEIBA in the laboratory. In the patients described here normalisation of the WBCT did not occur when the dose of FEIBA was less than 60 units/kg. Whether it is necessary to obtain complete correction of the WECT by FEIBA is still unclear; for example, Only partial correction of the WBCT was produced in the patient by 30 units/kg FEIBA. Nevertheless dental surgery was E&&m, without haemorrhagic complications.
650
FEIBA AND FACTOR VIII INBIBITOR
Vol.ll,No.5
An undesirable side effect of FEIBA was the stimulationof factor VIII inhibitor synthesis observed in the patient G.P. This occurred only after large concentrationsof the preparation had been given. It seems reasonable to ascribe the rise in inhibitor titre to FEIBA since no other blood products were given. In the three patients described here, the clinical responses to FEIBA have been extremely encouraging. Further clinical evaluation is obviously required as well as data relating to the monitoring of therapy. The dangers of possible thromboemboliccomplicationscannot be overstressed,particularly in patients with hepatic dysfunction. The increase in the factor VIII inhibitor presumably occurred as a consequenceof unwanted factor VIII in the preparation. It is to be hoped that this can eventually be excluded. ACKNOWLEDGEMENTS We wish to thank Immuno (Vienna)Ltd for generous supplies of FEIBA, and Professor G.1.C. Ingram for encouragement and advice.
1. 2.
3. 4. 5. 6.
7. 8.
mFERENCE8 GREEN, D. Spontaneous inhibitions of Factor VIII. Brit. J. bemat., J& 57, 1968. FEKETE, L.F., EGLST, S.L., PEETOOM, F., de VERBER, L.L. Fourteenth Internatio al Cow of wtoloov. Brazil, 1972. Abstract No. 295. KUICZYNSKI,E.M., PENNER, J.A. Activated prothrombin concentrate for patients with Factor VIII anti-bodies. New Enal. J. Ms@., a, 164, 1974. DACIE, J.V., LEWIS, S.M. Practical HaPmatoloov, 5th edn. Churchill Livingstone,Edinburgh, 1975. A quick and accurate method for ELLIS, B.C., STRANSEY, A. the determinationof fibrinogen in plasma. J. Lab. & Clin. !!&** 58, 477, 1961. Immunologicalstudies on FAGERECL, M.K., ABILDGAARD, U. human antithrcmbin III. Influence of age, sex and use of oral contraceptionon serum concentration. Stand. J. m., 1, 10, 1970. The treatment of patients who have RIZZA, C.R., BIGGS, R. Factor VIII anti-bodies. Brit. J. Haemat., 2, 65, 1973. IdXE, G.D.O., EARVIE, A., FORBES, C.b., PRENTICE, C.R.M. Case Report : Successful treatment with prothrcxnbin complex concentrate of post-operativebleeding in a haemophiliacwith Factor VIII inhibitors. Brit. Med. Jo, u, 1110, 1976.
vol.ll,No.5
9.
10.
11. 12. 13.
FEIBA AND FACTOR VIII INHIBITOR
651
Factor Eight inhibitor byA., LEWIS, M.J. Lancet, & 43, 1976. passing activity. Christmas factor concentrates TULLIS, J.L., BREEN, F. Bibliotheca the clinical use of several preparations. HasIpatolooica (Basel), 2, 40, 1970.
POLLOCK,
Prothrombin-complex concenMARCHESI, S.L., BURNFY, R. New Enal. J. Med., 290, 403, 1974. trates + thromboses. Vascular lesions in STEINBERG, M., DREILING, B.J. New Enal. J. Mea., 289, 592, 1973. Haemophilia B. Characterisation of HESS, K., SHIH, N., TISHKOFF, G. Factor VIII inhibitor by-passing activity (FEIBA). Abstract, VIth Cm of the International So 'etv of Thrombosis and Haemostasis. Philadelnhia, U.S.Ac'p.188 1977.
Vol.
RESEARCH
Printed
in Great
11, PP. 643-651, 1977 Pergamon
Britain
Press,
Ltd.
FACTOR VIII INBIBITOR BY-PASSING ACTIVITY (FEIBA) IN THE MANAGEMENT OF PATIENTS WITH FACTOR VIII INHIBITORS F.E. Preston*, *University Sheffield
R.C.W. Dinsdale**, P.J. Wyld* and
D.J. Sutcliffe*, J.F. Hamlyn**
G. Bardhan*,
Department of Haematology, The Royal Infirmary, ~6 3DA and **The Charles Clifford Dental Hospital, Sheffield SlO 2SZ England
(Received
14.7.1977; in revised form 1.9.1977. Accepted by Editor A.L. Bloom)
ABSTRACT Three patients with high titre factor VIII inhibitors have been treated with factor VIII inhibitor by-pass Successful management of sponactivity (FEIBM. taneous bleeding episodes was achieved in all three In one patient dental surgery was performed patients. three tips without haemotrhagic complications and on each occasion tbs only treatment given was FEIBA and The only complication of an antifibrinolytic agent. FEIBA has been a significant increase in the factor VIII inhibitor concentration of one patient. Disseminated intravascular coagulation did not occur*
INTRODUCTION
Factor VIII inhibitors occur in 6 - 8% of haemophiliacs. They may also occur spontaneously in the elderly or in patients with auto-immune or collagen disorders (1). Rs9ardless of ths underlying pathology the management of the haemorrhagic manifestations of patients with factor VIII inhibitors is notoriously difficult. Until recently the most satisfactory method of treating these patients was by attempting to neutralise the inhibitor with large amounts of factor VIII concentrate but even this is not always successful. Recently there have been a number of reports suggesting that prothrombin complex concentrates may be a useful alternative method of tnsating these patients (2,3). %ae we present details of our experience with factor VIII by-pass activity (FEIBA).
643
644
FEIBA ANB FACTOR VIII. INHIBITOR
Vol.ll,No.5
PATIENTS Patient 1 G.K., an 81 year old lady, had been perfectly well until June 1975, when she developed very severe bruising after a minor fall. During the next 14 months she complained of repeated and extensive spontaneous bruising which was of sufficient severity to warrant blood transfusion. During this period she also had a proven spontaneous haemarthrosis of the left knee. In August 1976 she was transferred to the Royal Infirmary, Sheffield, with a four week history of a gradually increasing spontaneous haematoma of the right breast. On admission her haemoglobin was 6.6 g/dl. The diagnosis of acquired haemophilia was established on the basis of F.VIII C 2%, F.VIII R.A. 105% and a factor VIII inhibitor 1080 u/ml. There were no abnormalities of any other clotting factor and platelet count and functions were both normal. There was no clinical or laboratory evidence of autoimmune disease. The anaemia was corrected by blood transfusion and she was observed for 48 hours. At this tims a painful and rapidly progressive spontaneous haematoma developed in the flexor aspect of the right forearm. This was associated with tingling and parasthesia of the fingers of the right hand. It was decided to give FEIBA 40 units/kg intravenously. Within four hours the pain had subsided and there was no further progression of the haematoma. The FEIBA was administered at the same dosage at eight-hourly intervals. The parasthesiae ceased 12 hours later. After five days the FEI8A was discontinued and two days later G.K's haemoglobin again began to fall and this coincided with a spontaneous haematoma of the left forearm. FEIBA was again administered at the same dosage as previously and again there was rapid clinical response. Patient 2 A.D., a 74 year old lady, was transferred to the Royal Infirmary, Sheffield, with a ten week history of recurrent sponShe gave a 14 year history of taneous bruising and epistaxis. rheumatoid arthritis for which she was receiving enteric-coated prenisolone, 5 mgm bd., ibuprofen, dextropropoWphens hydra- ’ A diagnosis of acquired haemophilia chloride and paracetamol. was established on the basis of F-VIII C 1.5%, F.VIII R-A. 11096 There were no abnormalities and factor VIII inhibitor 250 u/ml. of any other clotting factor, and platelet count and function On admission her haemoglobin was 7.5 g/alwere both normal. She was observed for approximately 10 days, during which time she required two blood transfusions for rapidly developing anaemia. During this period there was no haematological evidence of haemolysis and since.faecal occult blood were very strongly positive, it was considered that the rapidly developing anaemia Radiological investiwas due to gastrointestinal haemorrhage. gation of the gut failed to reveal the cause of the haemorrhage. After the second blood transfusion she was commenced on FEIBA, 40 units/Kg 8-hourly and this was continued for a period of ten As can be seen from Fig. 1, there was no further fall in days. At the end of the treatment her haemoglobin during this period. period the FEIBA was discontinued and she was commenced on During the following two weeks her immunosuppressive therapy.
645
FEIBA AND FACTOR VIII INHIBITOR
Vol.ll,No.5
general condition remained satisfactoryand‘& was eventually transferredback to the referring hospital. It was learned that she died two months later from massive gastrointestinal haemorrhage. An autopsy was not performed. E E.I.6.A 15, l4,
6_ 5,
,,,,,,,,,1,III,,11111111 15 17 19 21 23 25 27
29
1
3
5
7
8
OCt FIG. 1 The influence of FEIBA on the haemoglobin of a patient with gastrointestinalhwmrrhage associatedwith acquired haemophilia
Patient 3 G.P. is a known severely affected haemophiliac (F.VIII C < 1%) with a factor VIII inhibitor level of 12 u/ml. During 1976 he was frequently incapacitatedby recurrent spontaneoushaemarthroses and it was therefore decided to tnat all future joint bleeds with FEIBA. During the following sevenmonth period he received 24 treatments. Initially the dose of FEIBA was 14 units/kg, but satisfactoryclinical responses ware subsequentlyobtained with 7 units/kg. The results of this form of therapy appeared to be very encouraging in that there was rapid relief from pain and on no occasion did the haemarthrosis progress* G.P. himself was convinced that the joint bleeds were arrested by the treatment. In October 1976 he was seen by a dental surgeon on account of severe toothache. Total dental clearance was recommended and in view of the patient's previous responses to FEIBA, it was decided to use this product to cover the extractions. On the first occasion an upper second premolar was extracted using local anaestheticpmcmkd by intravenousFEIBA, 30 units/kg, and epsilon aminocaproicacid (EACA) 0.1 g/kilo. There was no imnsdiah or delayed haemorrhage. Oral EACA was continued, 6 g six-hourlyuntil the sutures were removed. Oral antibiotics WHZJ the only other drugs given during this period.
646
FEIBA AND FACTOR VIII INHIBITOR
Vol.ll,No.5
Six weeks later a first and second premolar and a second molar were extracted under FEIBA cover. EACA and antibiotics were administered as before. Intravenous FEIBA 60 units/kg was given immediately before the extractions which were performed under local anaesthetic. Eaemostasis was considered so satisfactory that it was decided to continue and an additional first molar was also extracted. This prolonged the operation by forty minutes since the tooth had large roots and the extraction was technically difficult. The post-operative period was uneventful apart from some slight oozing which occurred from a suture hole 24 hours after the extraction This was readily controlled by local measures and a further injection of FEIBA, 30 units/kg. Dental surgery was again undertaken three months later. This was performed under local anaesthetic preceded by intravenous FEIBA, 60 units/kg and EACA 0.1 g/kg. On this occasion five teeth were extracted - an upper right first and second premolar, first and second molars and an upper left first premolar. Both upper first premolars had three roots and a transalveolar approach was necessary on the left side, requiring incision and mucoperlosteal flap with suturing. There was no bleeding from this area post-operatively. On the right side there was some oozing from the soft tissues of the molar sockets which were the site of active periodontal disease with One further injection of FEIBA, 30 units/kg was hyperaemia. given twelve hours later and oral antibiotics were administered On this occasion oral antlfibrinolytic treatment as before. The was continued with tranexamic acid, 0.5 g six-hourly. post-operative course was uneventful and wound-healing was normal. ’ METHODS Basic haematological investigations, including tests of coagulation were performed as described by Dacie and Lewis (4). Plt?lz fibrinogen was quantitated by the Ellis Stranslcy (5) . Serum F.D.P's were measured by the Burroughs Wellcom F.D.P. kit. Plasma anti-thrombln III was measured by a radial Factor VIII antibodies were immunodiffusion technique (6). An assayed by the method described by Rizza and Biggs (7). antibody unit is defined as the amount of antibody which destroys 0.5 units of factor VIII after four hours incubation. Whenever possible, blood samples were taken before the administration of FEIBA and at 15 minutes, 60 minutes and 120 At each sampling the following tests were minutes post-FEIBA. performed : whole blood clotting tima (WBCT): thrombin clotting time: prothrombln time; kaolin-cephalln clotting tine: serum F.D.P's: plasma fibrinogen: anti-thrombin III and platelet count. Responses were assessed on seven separate occasions in patient G.P. and on three occasions in each of the The concentration of FEIBA varied from 13 other two patients. units/kg to 60 units/kg.
Vol.ll,No.5
FEXBA AND FACTOR VIII INBIBITOR
647
LABORATORY RESULTS At all FEIBA concentrationsgreater than 13 Units/kg of the whole blood clotting time significantimprovenuant occurred.fifteenminutes after infusion (Table 1). Generally, t& degree of correction related to the concentrationof the infused material but on no occasion was the WBCT completely normalised. At two hours some degree of correction of the WBCT was still evident. The kaolin-cephalinclotting time was also shortenedby FEIBA, but although the observed effect was proportioned to the concentrationof infused FEISA, it was usually less than the correspondingchange in the WBCT. WhenFEIBAwas mixed with the patient's plasma in the laboratorythere was significant shorteningof the KCCT and this was always greater than the correspondingin viva effect (Table 2). TABLE 1 Chahges in Whole Blood Clotting Time OJBCT) following FEIBA Infusion (PatientG.P.)
Pre Infusion (mins.) 13 13 13 20 30 30 60
33 24 24 30 22 36 35
WBCT Post Infusion (mins.) 29 22 22 15 16 21 13
%
Reduction
12 8 8 50 27 42 63
The prothrombin time was also shortened one or two seconds by FEIEA administration. There was no evidence of disseminated intravascularcoagulation in any of the 13 studies. In particular, platelet counts, plasma fibrinogen, anti-thranbinIII and serum F.D.P. remained unchanged for the period of investigation. &&$&&&&In!! of FEIBA The only c lication detected was a marked incre;yh;; the factor VIII % in bitor of patient G.P. (Fig. 2). patient no chenge occurred in the factor VIII inhibitor level during the first thnee months of treatment by FEIBA. f)uring this period 11 treatmentswere given, in most instances the
648
FEIBA AND FACTOR VIII INBIBITOR
Vol.ll,No.5
TABLE 2 Comparison of In Vitro and In Viva Effects of FEIBA on the KCCT
Patients
(sees. )
G.P.
G.K.
A.D.
195
120
190
KCCT (sacs.) 15 Post FEIBA infusion*
152
117
164
KCCT (sets.) Mixing Experiment Patient's plasma + FEIBA (1 unit/ml)
83
80
79
KCCT
*Dose 1 unit/ml plasma calculated on basis of blood volume 7QrWkg Following the first dental extraction dose being 7 units/kg. the inhibitor rose from 14 to 20 units/ml, but two months later it had receded to 12 units/ml. The second dental procedure was accompanied by a marked rise in the inhibitor to 48 units/ml. At no time has this patient received any other blood product.
Dental Extraction
Dental Extraction
50, 40 I Factor VIII Inhibitor (u/knl) 30, 20, 10 , JASONDJ 1976
1977
Fig. 2 Factor VIII inhibitor levels in patient GOP-
Vol.ll,No.5
FEIBA AND FACTOR VIII INHIBITOR
649
DISCUSSION
The treatment of patients with factor VIII inhibitors Recent reports on the use of is notoriously difficult. prothrombin complex concentrates and factor VIII by-passing fractions in the management of these patients is therefore of However, experience in their use considerable interest. remains limited and not all workers are convinced of the It is not always easy to efficacy of these products (3,8,9). Sponassess the therapeutic value of haemostatic agents. taneous cessation of bleeding in a haemophiliac is a recognized phenomenon and clinical evaluation of a concealed haemorrhage Thus the clinical responses of the is usually subjective. patients G.K. and A.D. may have been entirely fortuitous, although rapid regression of neurological symptoms in an inadeThe assessment of quately treated haemophiliac is unusual. post dental extraction haemorrhage thus offers considerable advantages since the bleeding site can be directly observed. Dental surgery is an effective haemostatic challenge and the absence of post extraction haemorrhage in a severely affected haemophiliac who has not received factor VIII cover is a rare The absence of bleeding in patient G.P. thus provides event. good evidence of the therapeutic efficacy of FEIBA, particularly since the unusual root formation of his molar and premolar teeth made the second and third operations extremely It may be argued that the antidifficult and time-consuming. fibrinolytic drugs were primarily responsible for maintaining Although this is a adequate haemostasis in this patient. possibility we believe that it is highly unlikely, particularly during the sacond and third operative sessions when substantial surgical manipulations were required. The reports of thromboses which have occurred in patients concentrate replacement therapy (10,11,12) receiving factor should temper enthusiasm for this form of treatment with considerable caution and evidence for unwanted activation of the In the coagulation mechanism should be carefully sought. ;zsts described here, FEIBA was administered at doses ranging - 60 u/kg. At these concentrations there was no clinical or laboratory evidence for intravascular coagulation. The mechanism by which FEIBA functions is unknown, although there is experimental evidence to show that it is not due to thrombin or the activated clotting factors Ix and x (13). resent state of knowledge it is difficult to monitor In the FEIBA tK erapy since the coagulation responses are somewhat unpredictable. In all instances the administration of FEIBA produced shortening of the activated partial thromboplastin time iFXJ$, the prothrombin time and the whole blood clotting time . The shortening of the APTT was always less than that observed when the patient's plasma was mixed with FEIBA in the laboratory. In the patients described here normalisation of the WBCT did not occur when the dose of FEIBA was less than 60 units/kg. Whether it is necessary to obtain complete correction of the WECT by FEIBA is still unclear; for example, Only partial correction of the WBCT was produced in the patient by 30 units/kg FEIBA. Nevertheless dental surgery was E&&m, without haemorrhagic complications.
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An undesirable side effect of FEIBA was the stimulationof factor VIII inhibitor synthesis observed in the patient G.P. This occurred only after large concentrationsof the preparation had been given. It seems reasonable to ascribe the rise in inhibitor titre to FEIBA since no other blood products were given. In the three patients described here, the clinical responses to FEIBA have been extremely encouraging. Further clinical evaluation is obviously required as well as data relating to the monitoring of therapy. The dangers of possible thromboemboliccomplicationscannot be overstressed,particularly in patients with hepatic dysfunction. The increase in the factor VIII inhibitor presumably occurred as a consequenceof unwanted factor VIII in the preparation. It is to be hoped that this can eventually be excluded. ACKNOWLEDGEMENTS We wish to thank Immuno (Vienna)Ltd for generous supplies of FEIBA, and Professor G.1.C. Ingram for encouragement and advice.
1. 2.
3. 4. 5. 6.
7. 8.
mFERENCE8 GREEN, D. Spontaneous inhibitions of Factor VIII. Brit. J. bemat., J& 57, 1968. FEKETE, L.F., EGLST, S.L., PEETOOM, F., de VERBER, L.L. Fourteenth Internatio al Cow of wtoloov. Brazil, 1972. Abstract No. 295. KUICZYNSKI,E.M., PENNER, J.A. Activated prothrombin concentrate for patients with Factor VIII anti-bodies. New Enal. J. Ms@., a, 164, 1974. DACIE, J.V., LEWIS, S.M. Practical HaPmatoloov, 5th edn. Churchill Livingstone,Edinburgh, 1975. A quick and accurate method for ELLIS, B.C., STRANSEY, A. the determinationof fibrinogen in plasma. J. Lab. & Clin. !!&** 58, 477, 1961. Immunologicalstudies on FAGERECL, M.K., ABILDGAARD, U. human antithrcmbin III. Influence of age, sex and use of oral contraceptionon serum concentration. Stand. J. m., 1, 10, 1970. The treatment of patients who have RIZZA, C.R., BIGGS, R. Factor VIII anti-bodies. Brit. J. Haemat., 2, 65, 1973. IdXE, G.D.O., EARVIE, A., FORBES, C.b., PRENTICE, C.R.M. Case Report : Successful treatment with prothrcxnbin complex concentrate of post-operativebleeding in a haemophiliacwith Factor VIII inhibitors. Brit. Med. Jo, u, 1110, 1976.
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Factor Eight inhibitor byA., LEWIS, M.J. Lancet, & 43, 1976. passing activity. Christmas factor concentrates TULLIS, J.L., BREEN, F. Bibliotheca the clinical use of several preparations. HasIpatolooica (Basel), 2, 40, 1970.
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Prothrombin-complex concenMARCHESI, S.L., BURNFY, R. New Enal. J. Med., 290, 403, 1974. trates + thromboses. Vascular lesions in STEINBERG, M., DREILING, B.J. New Enal. J. Mea., 289, 592, 1973. Haemophilia B. Characterisation of HESS, K., SHIH, N., TISHKOFF, G. Factor VIII inhibitor by-passing activity (FEIBA). Abstract, VIth Cm of the International So 'etv of Thrombosis and Haemostasis. Philadelnhia, U.S.Ac'p.188 1977.
