scholarly journals Use of porcine factor VIII in the treatment of patients with acquired hemophilia

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1513-1520 ◽  
Author(s):  
AE Morrison ◽  
CA Ludlam ◽  
C Kessler
Keyword(s):  
Factor Viii ◽  
Acquired Hemophilia ◽  
First Line Therapy ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Inhibitor Level ◽  
Clinical Responses ◽  
Bleeding Episodes ◽  
Antibody Levels ◽  
Auto Antibody

Abstract Data have been collected from 47 centers in Europe and North America on the treatment with porcine factor VIII concentrate of 74 acute bleeding episodes in 65 patients with acquired hemophilia. The median initial anti-human factor VIII auto-antibody inhibitor level was 38 Bethesda unit (BU)/mL (range 1.2 to 1,024) whereas that against porcine was 1 BU/mL (range 0 to 15). The mean initial dose of porcine factor VIII infused was 84 IU/kg, which increased the plasma factor VIII:C activity by 0.85 IU/mL. Therapy was continued for a mean of 8.5 days during which time the average number of infusions was 11. Objective clinical responses were rated as good or excellent in 78% of recipients. Side effects were uncommon; only one patient experienced a severe anaphylactic reaction necessitating the discontinuation of porcine FVIII therapy. After therapy, no increase in the median level of anti- human FVIII or anti-porcine antibody was noted in the group as a whole, although 13 patients showed individual increases in either anti-human or anti-porcine antibody levels or both of more than 10 BU/mL. Of the 7 patients who subsequently rebled, 5 were successfully re-treated and 2 did not respond to further porcine factor VIII treatment. Porcine factor VIII is safe and clinically effective treatment for bleeding episodes associated with acquired hemophilia and should be considered as first-line therapy for patients whose acquired anti-factor VIII:C antibody cross-reacts with porcine factor VIII:C at low levels.

scholarly journals Use of porcine factor VIII in the treatment of patients with acquired hemophilia

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1513-1520 ◽  
Author(s):  
AE Morrison ◽  
CA Ludlam ◽  
C Kessler
Keyword(s):  
Factor Viii ◽  
Acquired Hemophilia ◽  
First Line Therapy ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Inhibitor Level ◽  
Clinical Responses ◽  
Bleeding Episodes ◽  
Antibody Levels ◽  
Auto Antibody

Data have been collected from 47 centers in Europe and North America on the treatment with porcine factor VIII concentrate of 74 acute bleeding episodes in 65 patients with acquired hemophilia. The median initial anti-human factor VIII auto-antibody inhibitor level was 38 Bethesda unit (BU)/mL (range 1.2 to 1,024) whereas that against porcine was 1 BU/mL (range 0 to 15). The mean initial dose of porcine factor VIII infused was 84 IU/kg, which increased the plasma factor VIII:C activity by 0.85 IU/mL. Therapy was continued for a mean of 8.5 days during which time the average number of infusions was 11. Objective clinical responses were rated as good or excellent in 78% of recipients. Side effects were uncommon; only one patient experienced a severe anaphylactic reaction necessitating the discontinuation of porcine FVIII therapy. After therapy, no increase in the median level of anti- human FVIII or anti-porcine antibody was noted in the group as a whole, although 13 patients showed individual increases in either anti-human or anti-porcine antibody levels or both of more than 10 BU/mL. Of the 7 patients who subsequently rebled, 5 were successfully re-treated and 2 did not respond to further porcine factor VIII treatment. Porcine factor VIII is safe and clinically effective treatment for bleeding episodes associated with acquired hemophilia and should be considered as first-line therapy for patients whose acquired anti-factor VIII:C antibody cross-reacts with porcine factor VIII:C at low levels.

scholarly journals Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 31-41 ◽  
Author(s):  
PB Kernoff ◽  
ND Thomas ◽  
PA Lilley ◽  
KB Matthews ◽  
E Goldman ◽  
...  
Keyword(s):  
Factor Viii ◽  
Clinical Experience ◽  
Human Factor ◽  
Intermediate Level ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Post Infusion ◽  
Clinical Responses ◽  
Circulating Antibodies

Circulating antibodies to factor VIII (anti-VIII, “inhibitors”) occurring in patients with hemophilia neutralize porcine factor VIII less readily than human factor VIII in vitro. Over an 18-mo period, 8 patients with anti-VIII were treated with 45 courses (297 infusions) of polyelectrolyte-fractionated porcine factor VIII concentrate (PE porcine VIII). Where no anti-PE porcine VIII was detectable, mean post- infusion rise in plasma factor VIII was 1.29 U/dl/units infused/kg. Above 13 Old Oxford units of anti-PE porcine VIII and 48 Bethesda units of anti-human VIII, there were no postinfusion rises in plasma factor VIII. Where postinfusion rises were detected, clinical responses were good and conventional methods could be used to guide dosage. Ten percent of infusions were followed by febrile reactions, but these were usually mild and decreased in frequency and severity with increasing exposure. Multiple and prolonged courses of therapy were given to some patients without evidence of loss of clinical or laboratory efficacy. PE porcine VIII could provoke anamnestic rises of anti-VIII in susceptible patients, but appeared to have a lower immunogenic potential than human VIII. PE porcine VIII is a rational and effective therapeutic alternative for patients with anti-VIII, particularly those with intermediate level inhibitors who cannot be managed effectively using human factor VIII.

Polyelectrolyte Fractionated Porcine Factor VIII Concentrate In The Treatment Of Haemophiliacs With Antibodies To Factor VIII: C

1981 ◽  
Author(s):  
P B A Kernoff ◽  
N D Thomas ◽  
P A Lilley ◽  
E G D Tuddenham
Keyword(s):  
Factor Viii ◽  
Adverse Reactions ◽  
Human Factor ◽  
High Plasma ◽  
Major Drawback ◽  
Therapeutic Value ◽  
Human Factor Viii ◽  
Clinical Responses ◽  
Bleeding Episodes

Antibodies to procoagulant factor VIII (anti-VIII:C) occurring in patients with haemophilia neutralise porcine factor VIII:C less readily than human factor VIII: C in vitro. Porcine factor VIII concentrate (porcine VIII) therefore has potential advantages in the treatment of such patients. Polyelectrolyte-fractionated porcine VIII (PE porcine VIII) lacks a major drawback of earlier preparations of porcine VIII in that it contains negligible quantities of platelet aggregating factor (PAF). The purpose of this study was to make a preliminary clinical assessment of the therapeutic value of PE porcine VIII. Over 6 months, 12 courses of treatment were given to four patients with circulating anti-VIII: C. Bleeding episodes treated ranged from the potentially lethal to moderately severe joint and muscle haemorrhages. Duration of courses was from 24 hrs. to more than 3 weeks. Clinical responses were strikingly good and no patient developed thrombocytopenia. Occasional mild pyrogenic-type transfusion reactions were encountered, but these were easily controlled. Dose- response relationships were most favourable in patients with low pre-infusion levels of anti-VIII: C activity against PE porcine VIII but excellent clinical responses could be obtained without achieving high plasma VIII: C levels. Multiple courses of therapy (up to 6) were given to individual patients without evidence of loss of clinical or laboratory efficacy, or an increased tendency to adverse reactions. There was no evidence of resistance in the patient who was treated daily for more than 3 weeks. Only 1 course of therapy was followed by a classical anamnestic rise in anti-VIII: C, and this course had included human factor VIII. PE porcine VIII appears to have a low immunogenic potential, and is a rational and effective therapeutic alternative for patients with anti-VIII: C.

scholarly journals Clinical experience with polyelectrolyte-fractionated porcine factor VIII concentrate in the treatment of hemophiliacs with antibodies to factor VIII

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 31-41 ◽  
Author(s):  
PB Kernoff ◽  
ND Thomas ◽  
PA Lilley ◽  
KB Matthews ◽  
E Goldman ◽  
...  
Keyword(s):  
Factor Viii ◽  
Clinical Experience ◽  
Human Factor ◽  
Intermediate Level ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Post Infusion ◽  
Clinical Responses ◽  
Circulating Antibodies

Abstract Circulating antibodies to factor VIII (anti-VIII, “inhibitors”) occurring in patients with hemophilia neutralize porcine factor VIII less readily than human factor VIII in vitro. Over an 18-mo period, 8 patients with anti-VIII were treated with 45 courses (297 infusions) of polyelectrolyte-fractionated porcine factor VIII concentrate (PE porcine VIII). Where no anti-PE porcine VIII was detectable, mean post- infusion rise in plasma factor VIII was 1.29 U/dl/units infused/kg. Above 13 Old Oxford units of anti-PE porcine VIII and 48 Bethesda units of anti-human VIII, there were no postinfusion rises in plasma factor VIII. Where postinfusion rises were detected, clinical responses were good and conventional methods could be used to guide dosage. Ten percent of infusions were followed by febrile reactions, but these were usually mild and decreased in frequency and severity with increasing exposure. Multiple and prolonged courses of therapy were given to some patients without evidence of loss of clinical or laboratory efficacy. PE porcine VIII could provoke anamnestic rises of anti-VIII in susceptible patients, but appeared to have a lower immunogenic potential than human VIII. PE porcine VIII is a rational and effective therapeutic alternative for patients with anti-VIII, particularly those with intermediate level inhibitors who cannot be managed effectively using human factor VIII.

Durable Responses to Rituximab In Acquired Factor VIII Deficiency.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3680-3680
Author(s):  
Abha Goyal ◽  
Iyad S. Hamarneh ◽  
Mark W. Karwal ◽  
Steven R. Lentz
Keyword(s):  
Factor Viii ◽  
Complete Response ◽  
Factor Viii Inhibitor ◽  
Second Line ◽  
Acquired Hemophilia ◽  
Plasma Factor ◽  
Inhibitor Level ◽  
Viii Inhibitor

Abstract Abstract 3680 Introduction: Acquired hemophilia is a life-threatening condition caused by inhibitory autoantibodies against coagulation factor VIII. Successful management of this condition requires urgent treatment of bleeding episodes, usually with factor VIII bypassing agents, as well as long-term suppression of the autoantibody. The anti-CD20 monoclonal antibody rituximab is used as a second line agent to suppress autoantibody production, but little is known about the long-term effectiveness or toxicity of rituximab. Our group was among the first to report responses to rituximab in patients with acquired hemophilia (Karwal et al. Blood 2001; 98:533a). We now report the long-term follow-up of 7 patients with acquired factor VIII deficiency treated with rituximab. Methods: We retrospectively reviewed the medical records of 8 consecutive patients diagnosed with an acquired factor VIII inhibitor who had received rituximab as either first- or second-line immunosuppressive therapy at the University of Iowa between 1996 and 2004. Criteria for the diagnosis of acquired hemophilia included: 1) a plasma factor VIII activity (FVIII:C) level <0.5 U/mL, 2) a plasma factor VIII inhibitor level of greater than 0.5 Bethesda Units (BU), and 3) no prior history of hemophilia. Rituximab, 375mg/m2 intravenously, had been administered weekly for 4 to 6 doses. Complete response (CR) to treatment was defined as the attainment of a normal factor VIII level and an inhibitor level <0.5 BU. After obtaining informed consent, the patients or their representatives were contacted by telephone and asked to complete a verbal questionnaire to obtain follow up information. Follow-up data was obtained for 7 of the 8 patients. Results: Median follow up duration was 4.9 years. Median age was 77 years and 70% were female. Pre-rituximab factor VIII inhibitor titer ranged from 4 to 770 BU. Four patients had received prior immunosuppressive therapy with prednisone, cyclosporin, azathioprine, vincristine, and/or cyclophosphamide. A complete response was achieved in 6 of 7 patients (86%) with a median time to response of 10 months. No relapses had occurred in the 6 responders after 1.8 to 6.4 years of follow-up. Late-onset neutropenia was observed in 2 patients, 76 to 110 days after initiation of therapy, which is similar in time of onset to neutropenia reported in lymphoma patients treated with rituximab. Three patients died of causes unrelated to bleeding or infection. Conclusions: This study represents the longest duration of follow-up to date of patients with acquired hemophilia after treatment with rituximab. The initial response rate to rituximab was high (86%) and all of the responding patients remained in CR after a median follow-up of nearly 5 years. Because spontaneous remissions may occur in patients with acquired hemophilia, it is not possible to attribute all of the observed responses to rituximab. Nevertheless, we conclude from these findings that durable responses often occur when patients with acquired hemophilia are treated with rituximab. Disclosures: Off Label Use: rituximab for acquired hemophilia. Karwal:Genentech: Consultancy. Lentz:Novo Nordisk: Consultancy.

The Fractionation Properties of Human Factor VIII (Antihaemophilic Factor)

1960 ◽  
Vol 04 (02) ◽  
pp. 253-260 ◽  
Author(s):  
Franco Gobbi
Keyword(s):  
Factor Viii ◽  
Human Factor ◽  
Maximum Yield ◽  
Factor Vii ◽  
Precipitation Method ◽  
Salting Out ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Two Factors ◽  
Thromboplastic Activity

SummaryThe fractionation properties of human Factor VIII (antihaemophilic factor, AHF, antihaemophilic globulin) have been studied using a plasma of congenital afibrinogenaemia as a starting material.From a fibrinogen-free plasma, Factor VIII does not precipitate with ethanol at a final concentration of 8%; on the contrary the maximum yield is reached at an ethanol concentration of 25%.With a precipitation method carried out by a one to ten dilution of plasma with distilled water and acidification by N/10 hydrochloric acid to a pFI 5.2, Factor VIII does not precipitate with the euglobulin fraction; when normal plasma is used, such a precipitation is almost complete.With the salting-out fractionation method by ammonium sulphate, Factor VIII precipitates at a concentration between 25 and 33% of saturation either from fibrinogen-free and from normal human plasma.A non-specific thromboplastic activity appears in the fractions prepared by every method. This activity, which is probably due to the activation of seric accelerators, is easily removed by Al(OH)s adsorption. Thus, in order to insure the specificity of Factor VIII assays, the preliminary adsorption of the fractions is indispensable before testing their antihaemophilic activity.Fibrinogen and Factor VIII have different and definite precipitation patterns. When these two factors are associated the fractionation properties of AHF appear quite modified, showing a close similarity to those of fibrinogen. This fact can explain the technical difficulties encountered in the attempt to purify the antihaemophilic factor, and the lack of reproducible procedures for removing fibrinogen without affecting Factor VII.

scholarly journals Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion

Blood ◽  
1985 ◽  
Vol 65 (4) ◽  
pp. 823-831 ◽  
Author(s):  
VT Turitto ◽  
HJ Weiss ◽  
TS Zimmerman ◽  
II Sussman
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Vessel Wall ◽  
Platelet Adhesion ◽  
Human Factor ◽  
Rabbit Aorta ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Von Willebrand ◽  
Willebrand Factor

The present studies were undertaken to determine whether factor VIII/von Willebrand factor (vWF) present in the vessel wall (in addition to that in plasma) may mediate the attachment of platelets to subendothelium. Subendothelium from everted rabbit aorta was exposed to human citrated blood flowing through an annular perfusion chamber at 40 mL/min (wall shear rate of 2,600 s-1 for five minutes). The vessel segments were incubated at 37 degrees C for one hour with various dilutions of either goat-anti-rabbit factor VIII/vWF serum or an IgG fraction prepared from the serum. Control segments were incubated with serum or IgG from a nonimmunized goat. Values of platelet contact (C), platelet adhesion (C + S), and thrombus formation (T) on the subendothelium were evaluated by a morphometric technique. Compared with vessels incubated with fractions prepared from a normal goat, a significant decrease in platelet adhesion (C + S), ranging from 45% to 65%, was observed on vessels incubated with various dilutions (1:5 to 1:50) of either serum or IgG fractions of goat-anti-rabbit factor VIII/vWF. A similar decrease in platelet adhesion was observed with vessels incubated with an F(ab')2 fragment against rabbit factor VIII/vWF prepared in the goat. When goat-anti-rabbit factor VIII/vWF IgG was added to rabbit blood (1:75 dilution), platelet adhesion was reduced to the same extent (65%) on normal rabbit vessels and on vessels pre-incubated with goat-anti-rabbit factor VIII/vWF. Immunofluorescence studies revealed the presence of rabbit factor VIII/vWF in the subendothelium of rabbit aorta and the continued binding of the goat-anti-factor VIII/vWF antibodies on subendothelium during the perfusion studies. No uptake of human factor VIII/vWF on the rabbit subendothelium was observed by this immunologic technique; human factor VIII/vWF was found to be entirely associated with the attached human platelets. Thus, factor VIII/vWF in the vessel wall may mediate platelet attachment to subendothelium in a manner similar to that of plasma factor VIII/vWF.

Correction of the coagulation defect in hemophilia A mice through factor VIII expression in skin

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2799-2805 ◽  
Author(s):  
Steven S. Fakharzadeh ◽  
Yue Zhang ◽  
Rita Sarkar ◽  
Haig H. Kazazian
Keyword(s):  
Transgenic Mice ◽  
Factor Viii ◽  
Hemophilia A ◽  
Systemic Disease ◽  
Factor Viii Activity ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Transgenic Lines ◽  
Rag 1 ◽  
Involucrin Promoter

To test the hypothesis that factor VIII expressed in the epidermis can correct hemophilia A, we generated transgenic mice in a factor VIII–deficient background that express human factor VIII under control of the involucrin promoter. Mice from 5 transgenic lines had both phenotypic correction and plasma factor VIII activity. In addition to the skin, however, some factor VIII expression was detected in other tissues that have stratified squamous epithelia. To determine whether an exclusively cutaneous source of factor VIII could correct factor VIII deficiency, we grafted skin explants from transgenic mice onto mice that are double knockouts for the factor VIII and RAG-1 genes. Two graft recipients had plasma factor VIII activity of 4% to 20% of normal and improved whole blood clotting compared with factor VIII–deficient mice. Thus, expression of factor VIII from the epidermis can correct hemophilia A mice, thereby supporting the feasibility of cutaneous gene therapy for systemic disease.

Rabbit Antibodies Against the Procoagulant Activity (VIII:C) of Human Factor VIII

1981 ◽  
Vol 46 (04) ◽  
pp. 699-705 ◽  
Author(s):  
T H Tran ◽  
G A Marbet ◽  
F Duckert
Keyword(s):  
Factor Viii ◽  
Human Factor ◽  
Gel Filtration ◽  
Procoagulant Activity ◽  
Solid Matrix ◽  
Factor Viii Activity ◽  
Physiological Conditions ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Factor Viii Antigen

SummaryThe procoagulant activity VIII:C was separated from factor VIII antigen (VIIIR:Ag) by gel filtration in the presence of 0.25 mol/l calcium chloride. Antibodies (anti-VIII:C) were obtained by immunization of rabbits with VIII:C. The last step of the purification procedure of antibodies consists of an adsorption on VIIIR:Ag-Sepharose 2 BCL as immunoadsorbent to remove contaminating traces of antibodies against VIIIR:Ag. The anti- VIII:C titer remains unchanged during this adsorption (29 Bethesda units per mg). In solution, anti-VIII:C neutralies factor VIII activity (in plasma, cryoprecipitate or in purified form) and the fragment VIII:C without reacting with VIIIR:Ag. Once immobilized on a solid matrix, i.e.2% agarose, it loses over 95% of its inhibitory capacity. The immobilized anti-VIIIR:Ag binds stoichiometrically the antigen and the activity of plasma factor VIII. These results together suggest that factor VIII is composed of 2 different entities, but undissociated under physiological conditions. Immunophysical analyses as a function of pH and temperature of anti-VIII:C and its complex with factor VIII show properties similar to those of homologous antibodies. The antigen determinants of VIII:C (VIII:CAg) are destroyed at low pHs or high temperatures, and VIII:C can no more form a complex with anti-VIII:C. Purified anti-VIII:C is also used in a two-stage assay to detect VIII:CAg or cross-reacting material in some severe haemophiliacs.

scholarly journals Apparent molecular weight of purified human factor VIII procoagulant protein compared with purified and plasma factor VIII procoagulant protein antigen

Blood ◽  
1983 ◽  
Vol 62 (5) ◽  
pp. 1114-1117 ◽  
Author(s):  
MJ Weinstein ◽  
CA Fulcher ◽  
LE Chute ◽  
TS Zimmerman
Keyword(s):  
Molecular Weight ◽  
Factor Viii ◽  
Apparent Molecular Weight ◽  
Discontinuous System ◽  
Major Band ◽  
Molecular Weights ◽  
Human Factor Viii ◽  
Plasma Factor ◽  
Factor Viii Concentrates ◽  
Electrophoretic Techniques

Abstract We have compared apparent molecular weights of purified factor VIII procoagulant protein (VIII:C) and VIII:C antigen (VIII:CAg) by two different NaDodSO4 gel electrophoretic techniques. In a discontinuous NaDodSO4–7.5% polyacrylamide system, reduced and unreduced VIII:C, purified from commercial factor VIII concentrates by a monoclonal antibody immunoadsorption technique, showed a major doublet at mol wt 0.79 and 0.8 X 10(5) and less intense bands extending up to 1.9 X 10(5). In NaDodSO4–4% polyacrylamide/0.5% agarose gels (NaDodSO4–4% PAAGE), purified VIII:C had a major band of mol wt 1.0 X 10(5), with minor bands of mol wt 0.96, 1.1, 1.4, 1.6, 1.8, 2.2, and 2.4 X 10(5). In NaDodSO4–4% PAAGE of 125I-anti-VIII:C-Fab-VIII:CAg complexes, the major and minor forms of VIII:CAg in purified VIII:C had the same molecular weight as above when calculated by subtracting the molecular weight of 125I-Fab from 125I-Fab-VIII:CAg. In both plasma and factor VIII concentrate, a band of mol wt 2.4 X 10(5) predominated, and minor VIII:CAg forms of mol wt 2.6, 1.8, 1.2 and 1.0 X 10(5) were also visible. We conclude that the molecular weight of plasma VIII:CAg forms agree with those derived from protein stains of purified VIII:C in the NaDodSO4–4% PAAGE system, but that consistently lower molecular weight values are obtained for purified VIII:C in the discontinuous system. Both native and either disaggregated or proteolyzed VIII:C species are present in the purified VIII:C preparation.

Sign in / Sign up

Export Citation Format

Share Document