Porcine Factor VIIIC in the Management of Patients With Factor VIII Inhibitors

Porcine Factor VIIIC in the Management oC Patients With Factor VIII Inhibitors Charles R.M. Hay and Paula Bolton-Maggs

IRCULATING antibodies to factor VIIIC (inhibitors) arise in up to 20% of hemophilia A patients l - 3 and also in nonhemophilic patients in whom they are often found in association with autoimmune disease or malignancy. 4-6 Such inhibitors may render the patient refractory to treatment with conventional factor VIII replacement therapy by rapidly neutralizing infused factor VIIIC. A bewildering selection of blood products are available for the treatment of bleeding episodes in such patients, including human VIIIC,I-3,7.8 porcine VIIIC,9-11 prothrombin complex concentrates (PCCs), 12-14 and factor VIIa concentrates. 15 ,16 No single mode of therapy is suitable in all patients in all circumstances. Large doses of human factor VIIIC are effective in patients with low-Ievel inhibitors, but can cause a pronounced anamnestic response in susceptible individuals and are ineffective in patients with intermediate or high-Ievel inhibitors. I-3 ,7,8 Although prothrombin complex concentrates (PCCs) are less likely to eause an anamnestie response, they are cost1y, do not confer striking clinical benefit, 12-14 and their use has been associated with unaeceptable activation of eoagulation and myocardial infaretion. 14 Reeombinantor plasma-derived factor VIIa coneentrates appear more effective than PCCs, but are unsuecessful in up to a third of bleeding episodes and are not amenable to laboratory monitoring. 15 -16 Immunetolerance to human VIIIC can be achieved in some inhibitor patients, particularly those with low or intermediate-level inhibitors by regular administration of VIIIC eoncentrate over a period of weeks or months. 7,17-19 Porcine factor VIII concentrate was first prepared in the 1950s primarily as an altemative to human plasma-derived VIIIC, which was then, as now, in short supply, but also for the treatment of factor VIII inhibitor patients. 20,21 Antihuman factor VIIIC inhibitors are not specific for human factor VIII and usually cross-reaet to a variable extent with VIIIC from other species. Most faetor VIII inhibitors reaet less strongly with porcine VIIIC than with human VIIIC. 22 This confers the therapeutic advantage that porcine VIIIC is neutralized more slowly and less eompletely than human

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VIIIC. These concentrates were used with good effect to prevent bleeding in hemophiliacs both with and without faetor VIII inhibitors. 21 ,23 These early products had a number of serious disadvantages that limited their use to perhaps one or two occasions in a given patient's lifetime. Most serious was their tendency to cause severe reactions and "resistance" to treatment. 24 The cause of this resistance, decreased in vivo recovery in the absence of an increase in the inhibitor level occurring about a week after the beginning of therapy, was undear. The phenomenon was thought by Kemoff to be caused by an immunologie response mounted to non-VIIIC-related antigenie determinants (VIIIRA) in the faetor VIII complex. 25 Aeute postinfusion thrombocytopaenia also eomplicated treatment with porcine VIIIC in some patients, This was caused by platelet aggregating factor (PAF), a functional property associated with von Willebrand faetor antigen (vWFAg).26,27 These problems caused porcine factor VIII concentrate to fall into disuse, and it was not until these problems were largely resol ved by polyelectrolytefractionation of porcine factor VIIIC that interest in this modality of therapy revived. POLYElECTROlYTE PORCINE FACTOR VIII CONCENTRATE

Insoluble, cross-linked polyelectrolytes have been used for plasma fractionation since 1978. 28 The solid phase of a flexible fractionation system is eomposed of repeating units of ethylene maleic anhydride eopolymer in which the charge density can be varied by variable substitution of anhydride subgroups with positively eharged dimethylaminopropylimide. By adjusting pH, ionic strength, and charge density on the polyelectrolyte, a fractionation system is established for relatively largeFrom the Department oj Haemato1ogy, University oj Liverpool. Liverpool, England. Address reprint requests to Charles R.M. Hay. MD, Department oj Haematology, University oj Liverpool, The Duncan Building, Royal Liverpool Hospita1, Prescot St, Liverpool, L693BX. United Kingdom. Copyright © 1991 by W.B. Saunders Company 0887-796319110502 -0005$03 .0010

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scale production of highly purified plasma proteins. Using cryoprecipitate as the starting materiał, prothrombin complex factors are adsorbed to alumina and VIIIC adsorbed to polyelectrolyte (PE). After extensive washing, VIIIC is eluted from the column using l mollL sodium chloride, concentrated by polyethyline glycol precipitation and freeze-dried. 29 A key point in the production of PE porcine factor VIII is that VIIIC is adsorbed to PE, whereas there is very little adsorption of VIIIRA and PAF. PE fractionation yields porcine factor VIII concentrate (Hyate:C, Porton Speywood Ltd, Wrexham, Clwyd, Wales) of high purity and a specific activity of greater than 140 U VIIIC per milligram protein, typically containing 25 !-Lm VIIIC for every unit of VIIIRA. 3o SAFETY

Reactions and thrombocytopenia are seen much less frequently with PE porcine VIIIC than with the earlier preparations, and resistance to treatment has been reported in only three patients9-11 since the product was introduced. Reactions are reported following 7% to 13% of infusions with fewer reported in later series. 9-11 These are usually mild self-limiting febrile reactions, although more severe reactions, and even anaphylaxis, have been observed rarely. II.3I,32 These dinical characteristics suggest that contaminants such as pyrogens and endotoxins are more likely to have a causal role than porcine VIIIC or VIIIRA per se, although the reactions do not appear to be batch-related. Their severity and frequency appear to lessen with successive infusions and if the infusion is given slowly. Postinfusion thrombocytopenia is still occasionally observed, following 5 of 809 infusions reported in the three principal series. 9-11 The decrease in the platelet count was usually small and did not generally complicate the dinical course or management. A decrease in platelet count did not accompany every treatment episode in affected individuals and was not batch-related, suggesting a possible interaction between small quantities of contaminating vWF and products of damaged tissue. 27 The frequency and severity of transfusion reactions and thrombocytopenia with porcine VIIIC have decreased over the past few years. 11 ,31 These events are now uncommon and rarely of sufficient severity for therapy to be discontinued. This re-

duced frequency of reactions may refłect the increase in product purity in recent years from 25 !-Lm/mg in 1980 10 to greater than 140 !-Lm/mg in 1989. 30 Pigs do not carry human hepatitis viruses or human immunodeficiency virus (HIV), and porcine factor VIII concentrates have not been shown to transmit these infections,9-11,3I,33 nor do they transmit porcine viruses pathogenic to humans. Inhibitor patients treated exdusively with this product during the early 1980s have remained HIVseronegative. 33 Porcine VIIIC has also been used successfully to avoid infection with hepatitis viruses or HIV in previously untreated patients with mild hemophilia lacking factor VIII inhibitors. 34 CROSS-REACTIVITY AND INHIBITOR ASSAY

As might be expected, patients with low crossreactivity and low inhibitory activity against porcine VIIIC respond most favorably to treatrnent. The kinetics of interaction between porcine VIII and human inhibitors are usually of the "complex" type, and even at nominałly high-measured levels of inhibitor, significant residual levels of factor VIII may sometimes be detectable many hours after infusion. 31 Such persisting low levels of factor VIII activity may explain the favorable dinical responses often observed despite highlevel antiporcine inhibitors. The range of cross-reactivity is large, varying from 0% to 80%. High degrees of cross-reactivity are fortunately uncommon before treatment with porcine VIIIC, and 28% of inhibitor patients with congenital hemophilia A have no measurable antibody activity to porcine VIIIC 9-11 (Fig l). Mean cross-reactivity has been reported to be between 15% and 32%.9-11 The recent large multicenter trial of Brettler et alI I reported significantly lower mean cross-reactivity than the earlier and smaller studies. 9. 10 The degree of cross-reactivity observed in the 56 patients with congenitał hemophilia A reported in these three studies is illustrated in Fig 1. Cross-reactivity may change after treatment, particularly in the context of an anamnestic response following a prolonged course of therapy. The degree of cross-reactivity is usually far less in acquired hemophilia A than that found in congenital hemophilia A. 9-II ,31 Ludlam and Morrison (personal communication, 1990), collating the European experience of patients with acquired hemophilia treated with porcine VIIIC, have described

FACTOR VIII INHIBITOR MANAGEMENT

147

30

28 26 24

22 20

ł

I

18 16

'5

J

14

E

12

i

10

~ [1J[1J[J 0-10

1'·20

21-30

31-40

41-50

51-60

61-70

70-50

% Cross Reactivity

Fig 1. Cross-reactivity ot inhibitors against porcine VIIIC in 56 patients with congenital haemophilia A. Mean crossreactivity ± SD 20 ± 21.5%; 16 patients show no crossreactivity (28.6%1, Data trom Gatti at al.' Kernoff et al.'o and Brettler et al. 11

21 patients whose mean eross-reaetivity was only 0.93%. The postinfusion recovery of poreine VIIIC was generally exeellent, a mean dose of 95 !Lm/kg resulting in a mean rise of factor VIIIC to 1.03 !Lm/kg. Poreine VIIIC is thus the replacement therapy of choice in most patients with acquired hemophilia A. The antibody aetivity to poreine VIIIC eannot be predieted from the inhibitor level measured with human VIIIC, sinee some patients with very high antihuman VIIIC inhibitor levels may have insignificant activity against porcine factor VIII and still obtain an excellent response. 9 - 11 ,31,32 This emphasizes the importanee of assaying inhibitory activity against both human and poreine factor VIII before deciding on optimal therapy for an individual patient. Inhibitory aetivity against porcine VIIIC is usually measured using a Bethesda assay in which reconstituted porcine factor VIII concentrate diluted in faetor VIII deficient plasma is used as the substrate. This assay technique eompares similar types of substrate, thus avoiding the marked discrepancy that has been observed between inhibitor aetivities measured against human plasma and human eoncentrate. IMMUNOGENICITY

Porcine factor VIII appears to be less immunogenie than human factor VIII in most hemophilic

patients. An anamnestic increase in antihuman VIIIC antibody is seen in approximately 25% of patients treated with poreine VIIIC. 9-11 ,33 Anamnesis oeeurred after as many as 40% of infusions in one series,9 but in only 18% of bleeding episodes reported in a more recent multieenter triaI. 11 Individual patients are variable in their antibody response to porcine VIIIC and may behave differendy in this respeet on different oeeasions. 9-11 Anarnnesis eannot be predieted from preinfusion antiporeine or antihuman faetor VIII levels and is unrelated to either the quantity of porcine VIIIC or the duration of therapy.9-11,31,33 Patients laeking measurable cross-reactivity to porcine VIIIC before treatment may be less likely to mount an anamnestie response. 33 Anarnnestic increases in antihuman VIIIC antibodies following poreine VIIIC therapy are unusual in acquired hemophilia A9-11 ,35.36 (A.E. Morrison and C.A. Ludlam, personal eommunication, 1990) in contrast with congenital hemophilia A, although there is no differenee between the two groups in the incidenee of specific antiporeine inhibitors following sueh treatment. Speeies-specific antiporeine VIIIC inhibitors mayaIso arise, particularly following prolonged eourses of treatment. These sometimes exceed the antihuman inhibitor titer and may render the patient refraetory to treatment with porcine VIII. Sueh inhibitors are not necessarily a eontraindication to eontinued treatment since effective hemostasis may be achieved despite the anamnestie response. 37 The inhibitors have been observed to disappear in some patients if treatment with porcine VIIIC continues, suggesting that it is possible to induee immune tolerance to porcine VIIIC by continued treatmene 3 in much the same way that continued treatment with human VIIIC may result in the disappearanee of antihuman VIIIC inhibitors. 17-19 CLlNICAL RESPONSE AND TREATMENT STRATEGY

The effieaey of porcine VIIIC in seleeted patients with eongenital hemophilia A and in acquired hemophilia is well established and is supported by three large studies and numerous smaller series. 9-11,33,35-39 Kemoff et al,1O studying eight patients over 18 months, reported suceess in 40 of 45 eourses, 20 of which were judged to be equivalent to the response normally expected in nonin-

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hibitor patients. Gatti et a1 9 obtained similar results in 16 "high responder" patients. A recent large United States multicenter study of 30 hemophilia A patients and 8 with acquired inhibitors treated for 45 bleeding episodes showed improvement in 90%, with an excellent response in 54%. Treatment failed in only one patient. II Adequate circulating levels of factor VIII were observed following treatment in 90% of these patients. 11 The clinical response to treatment with porcine VIIIC correlates directly with postinfusion plasma factor VIII levels and inversely with preinfusion inhibitor levels. The most appropriate treatment is selected on the basis of serial periodic measurements of inhibitor activity to human and porcine VIIIC wherever possible. Porcine VIIIC is arguably the treatment of choice in inhibitor patients lacking cross-reactivity (Table 1).33 Clinical and laboratory responses in this group are comparable with those observed with human factor VIIIC infusions in noninhibitor patients. 9-11 ,3I,33 Recovery of 1 to 1.5 !Lm/dUU of porcine VIIIC and half-life of 10 to 12 hours are typical of such patients. Although recovery is less and half-dis appearance time of porcine VIIIC more rapid in patients with detectable antiporcine inhibitor activity, a favorable clinical response is observed in most patients with less than 10 to 15 Bethesda units (BU) of antiporcine inhibitor activity (Table l). Clinical and laboratory responses may improve with subsequent infusions, presumably because circulating inhibitor is progressively neutralized. Although the absence of a detectable increment in factor VIII level 10 minutes after the end of the infusion is generally predictive of a poor response, Table 1. Treatment Policy for Initial Management of Factor VIII Inhibitor Patients Pretreatment Inhibitor Level (BU)

Antiporcine Antihuman Antiporcine

O <5 <5

Antihuman Antiporcine

5·50 '-15

Antihuman Antiporcine

> 15

>50

Firot Choice Blood-Produet and Initial Oooage

Porcine VIIIC 20 to 50 ~m/kg Mild/moderate episodes: human VIIIC 20 to 50 ~m/kg Severe episodes: porcine VIIIC 20 to 50 jl.m/kg Porcine VIIIC 20-100 ~m/kg PCCs/APCCs 50 jl.m/kg may be considered for mild episodes PCCs/APCCs 50 ~m/kg or Vlla concentrate 50-80 ~g/kg 4 hou rly or porcine VIIIC 100 ~m/kg

there are many anecdotal reports of a favorable clinical response in high-level inhibitor patients in whom large doses of porcine factor VIIIC apparently failed to affect the factor VIII level. ll ,31.37 High doses of porcine factor VIIIC should therefore be considered in patients with high-level factor VIII inhibitors who have failed to respond to other modalities of therapy. The dose of porcine VIIIC can be calculated either using an equation that relates the desired postinfusion factor VIII level to the number of units of porcine VIIIC to be infused,9 or using an empirical initial dose based on the clinical assessment and the last measured inhibitor level. 31 The former approach suffers the disadvantage that it requires predetermined inhibitor levels. In addition, the assumptions underlying this formula regarding dose-response relationships and the neutralizing capacity of the inhibitor are rough approximations, at best. The latter, more practical approach, has the great virtue that it enables the clinician to treat the patient as an emergency, using a "best guess" dose ranging from 10 to 100 !Lm/kg based on the patient's clinical status and most recent inhibitor estimation. The patient's current inhibitor level and the postinfusion factor VIIIC increment are assessed immediately following the first infusion and form the basis for subsequent dosing. There is no treatment applicable in all clinical situations and at all inhibitor levels, and thus the choice of the most appropriate blood product to use in individual patients must be kept under constant review. The patient's current or most recent inhibitor level and the severity of the clinical problem are the two most important factors that influence this choice. Previous responses to treatment should also be considered. Either human or porcine VIIIC should be used wherever they are likely to give a measurable increment in factor VIIIC level, since clinical responses superior to those obtained with activated (A) PCCs are invariably observed when circulating levels of VIIIC are achieved. Although the unit cost of porcine VIIIC is twice that of intermediate purity human factor VIIIC, and similar to that of monoclonally immunopurified factor VIII concentrate, it is a cost-effective altemative to the high doses of human factor VIIIC often used in inhibitor patients. Patients with low-level, low-responding inhibitors are generally treated with human factor VIIIC,

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although porcine VIIIC, 20 to 50 fJ.m/kg, should be considered for the treatment of serious bleeding episodes. It can be argued that porcine VIIIC is the blood product of choice for patients lacking crossreactivity, since this is the only product to which they will have anormai hemostatic response. Patients with intermediate level inhibitors (5 to 50 BU against human VIIIC, < 15 BU against porcine VIIIC) should be treated with APCCs for minor bleeding episodes to avoid anamnesis, and porcine VIIIC 50 to 100 fJ.mJkg for more severe bleeding episodes. The choice of prothrombin complex concentrate (PCC) or APCC is based on the patient's previous response to these products, but PCCs are preferred in those patients who respond to them. These patients should also be considered for induction of immune tolerance using regular factor VIlIC infusions. Patients with high-level, high-responding inhibitors (>50 BU against human VIIIC, > 15 BU against porcine VIIIC) remain a considerable therapeutic problem. APCCs can be used for minor bleeding problems, but are usually ineffective for severe bleeding episodes or surgery.12-14 In these circumstances, porcine VIIIC 100 fJ.m/kg should be considered, although VIIa and Xa concentrates may supersede both porcine VIIIC and APCCs in this situation. 15-16 There will remain a small number of patients for whom there is no effective treatment. Gur current strategy for the treatment of inhibitor patients is summarized in Table 1. NEWER INDICATIONS FOR THE USE OF PORCINE VIIIC

Porcine VIIIC has usually been used for the treatment of more serious bleeding episodes in patients with low- or intermediate-level inhibitors. The potential side effects have discouraged clinicians from using it for the treatment of routine bleeds and in a home-care setting. Given that these side effects are uncommon and seldom clinically significant, porcine VIIIC should be used more widely in selected patients. We have recent1y reported a group of five hemophilic patients treated exclusively with porcine VIIIC over periods of between 2 and 8V2 years. 33 All five had high-level, high-responding antihuman factor VIIIC inhibitors lacking antiporcine VIIIC activity. Porcine factor VIII therapy began in each patient when they were refractory to human factor VIIIC, when other treatment modalities had

failed, and when their deteriorating clinical state demanded more active therapy. Porcine factor VIIIC was given under hospital supervision at first, progressing to home therapy after a few months when no problems were encountered. The dosage schedule varied from 50 JJ.m/kg/d as prophylaxis and 20 fJ.m/kg on demand according to the clinical status of the patient, and the physician's preference. No significant thrombocytopenia, and no transfusion reactions were encountered. No anamnestic rise in antihuman VIIIC inhibitor was observed (Fig 2). Although specific antiporcine inhibitor activity rose in all five patients, this was generally transient, and only one patient became refractory to treatment. This suggests that the patients had become tolerant of porcine VIIIC. The induction of immune-tolerance in patients with antiporcine factor VIIIC inhibitors probably follows much the same principles and the induction of immunetolerance in patients with antihuman VIIIC inhibitors by repeated exposure to human VIIIC. A further important observation from this study was that all five patients lost their original antihuman factor VIII inhibitor. A typical example ofthe inhibitor responses from one of these patients over a 9-year follow-up period is illustrated in Fig 2. Surprisingly, there was no recurrence of antibody activity in three patients in whom human factor VIIIC home therapy was reestablished, despite the fact that all three had high-responding inhibitors before starting porcine factor VIIIC therapy (Fig 2). This suggests that treatment with porcine VIIIC

10

Fig 2. Inhibitor levels, 1980 through 1989, in I typical HIV· 1-seronegltive factor VIII inhibitor pltient with I noncross-relcting inhibitor, treltad for 6 yelrs with porcine VIIIC. 1-) HumIn inhibitor, (---) porcine inhibitor. Reprintad with permission. 33

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may have resulted in tolerance to human VIIIC in these patients. Tolerance develops to specific antigenic determinants and not specific antigens. Tolerance to one antigen may therefore be induced by the administration of immunogenic doses of a second antigen sharing the epitope to which the patient had originally been immunized. Porcine VIIIC may have induced tolerance to human VIIIC in this way and may have a limited role in the induction of tolerance in inhibitor patients with little or no cross-reactivity to porcine VIIIC. We consider porcine VIIIC to be the treatment of choice in hemophilic patients whose factor VIII inhibitors have little or no cross-reactivity. Twenty-eight percent of inhibitor patients fall into this category9-11 ,33 (Fig 1). There is nowaiso limited experience with the use of porcine factor VIII, 10 to 50 f1mJkg, on demand, in hemophilic patients with up to 30% cross-reactivity for the treatment of routine bleeding episodes over periods of several years 40 (Y. Laurian, B.T. Colvin, P.B.A, Kemoff, personal communication, 1989). This treatment is well t01erated, although cross-reactivity may change and specific antiporcine inhibitors may arise, particularly following a period of intensive therapy. This form of therapy deserves further investigation.

CONCLUSION

Porcine VIIIC has an established role as inpatient therapy of bleeding episodes in inhibitor patients with both acquired and congenital hemophilia A. Its effects and dosage are relatively predictable and can be monitored in the laboratory, a particular advantage over APCCs and VlIa concentrates. Porcine VIIIC is particularly useful in acquired hemophilia A in which the low degree of cross-reactivity and low incidence of anamnesis generally found in this group make it the replacement therapy of choice in most patients. Porcine VIIIC is generally well tolerated, reactions being few and generally very minor. Given these advantages, porcine VIIIC will probably come to be used more widely than formerly, and more frequently in a home-care setting. Some patients with cross-reacting and noncross-reacting inhibitor antibodies tolerate regular porcine VIIIC therapy in a home-care setting over a period of years, Some of these patients, particularly those with non--cross-reacting antibodies, may lose their inhibitors, Porcine VIIIC may therefore have a limited role in the "desensitization" of inhibitor patients lacking antiporcine VIIIC activity.

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recombinant factor VIIa in patient with severe haemo-philia during a synovectomy. Lancet 2:1193-1196, 1988 17. Ewing NP, Sanders NL, Dietrich SL, et al: Induction of jmmune tolerance to factor VIII in haemophiliacs with inhibitors. JAMA 259:65-68, 1988 18. Leewen EF, Mauser-Bunschotten EP, van Dijken PJ, et al: Disappearance of factor VIIIC antibodies in patients with haemophilia-A upon frequent administration of factor VIII in intermediate or low dose. Br J Haematol 64:291-297, 1986 19. Brackman HH, Egli H: Treatment of Haemophilia patients with inhibitors, in Seligsohn V, Rimon A, Horoszowski H (eds): Haemophilia. London, United Kingdom, Castle House, 1981, pp 113-120 20. Bidwell E: The purification of antihaemophilic globulin trom animaI plasma. Br J Haematol 1:386-387, 1955 21. MacFarlane RG, Biggs R, Bidwell E: Bovine antihaemophilic globulin in treatment of haemophilia. Lancet 1:1316, 1954 22. Bennet B, Ratnoff WD: Immunological relationships of anlihaemophilic factor of different species detected by specific human and rabbit antibodies. Proc Soc Exp Biol Med 143:701706, 1973 23. Fraenkel GJ, Honey GE: Gunshot wounds in a haemophilic patient. Successful treatment animaI antihaemophilic globulin and surgery. Lancet 2:1117-1121,1955 24. Bidwell E: Immunological aspects of haemophilia, in Biggs R, Macfarlane RE, (eds): Treatment of Haemophilia and Other Coagulation Disorders. New York, NY, Blackwell, 1966, p 98 25. Kernoff PBA: The factor VIII-related antigen and anlibodies to factor VIII, MD thesis, University of London, 1974 26. Evans RJ, Austen DEG: Assay and characterisation of the factor in porcine and bovine plasma which aggregates human platelets. Br J Haematol 36:117-126, 1977 27. Altieri DC, Capitanio AM, Mannucci PM: von WilIebrand factor contaminating porcine factor VIII, concentrate (Hyate:C) causes platelet aggregation. Br J Haematol 63:703711, 1986 28. Johnson AJ, Macdonald VE, Semar M, et al: Prepara-

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tion of the major plasma fractions by solid-phase polyelectroIytes. J Lab Clin Med 92:194-202, 1978 29. Middleton S: Polyelectrolytes and preparation of factor VIIIC, in Forbes CD, Lowe GDO, (eds): Unresolved problems in haemophilia. Lancaster, England MTP Press, 1982, pp 109120 30. Manufacturers information: Porton Speywood Ltd, Wrexham, Clwyd, Wales 31. Kernoff PBA: The c1inical use of porcine factor VIII, in Kasper CK (ed): Recent Advances in Haemophilia Care. Progress in C1inical and Biological Research, vo1324. Alan R. Liss, New York, 1990, pp 47-56 32. Erskine JG, Davidson JF: Anaphylactic reaction to lowmolecular-weight porcine factor VIII concentrates. Br Med J 389:2011, 1981 33. Hay CRM, Laurian Y, Verroust F, et al: Induction of immune-tolerance in patients with haemophilia A and inhibitors treated with porcine VIIIC by home therapy. Blood 76:882886, 1990 34. Bum AM, Cottrell SE, Maugham L, et al: The use of porcine VIIIC (Hyate:C) to treat haemophilia A patients without inhibitors. La Ricerca in Clinica e in Laboratorio 16:210, 1986 35. Hu\tin MB, Hennessey J: The use of polyelectrolytefractionated porcine factor VIII in the treatment of a spontaneously acquired inhibitor to factor VIII. Thrombosis Res 55:51, 1989 36. Hoyle C, Ludlam CA: Acquired factor VIII inhibitor associated with multiple sclerosis successfully treated with porcine factor VIII. Thromb Haemost 57:233, 1987 37. Boylen AL, Ewing NP, Kasper CK: Porcine VIIIC provided effective surgical haemostasis despite anamnestic response. Prog Clin Biol Res 150:378-381, 1984 38. Ciavarella N, Antoncecci S, Ranierri P: Efficacy ofporcine factor VIII in the management of haemophiliacs with inhibitors. Br J Haematol 58:641-648, 1984 39. Colvin BT, Ainsworth M, Buckley C: Experience with highly purified porcine factor VIII in a palient with haemophilia A and a factor VIII inhibitor. Clin Lab HaematoI5:55-59, 1982