Management of Haemophilia A with Antibodies - The Effect of Combined Treatment with Factor VIII, Hydrocortisone and Cyclophosphamide

1985 ◽  
Vol 54 (04) ◽  
pp. 776-779 ◽  
Author(s):  
U Hedner ◽  
L Tengborn
Keyword(s):  
Factor Viii ◽  
Combined Treatment ◽  
Factor Ix ◽  
Treatment Schedule ◽  
High Antibody ◽  
Anamnestic Response ◽  
Short Intervals ◽  
Low Responders ◽  
Antibody Levels ◽  
High Responders

SummaryImmune tolerance has by several methods been induced in haemophiliacs with antibodies. A conversion of “high responders” into “low responders” was previously reported after repeated moderate factor IX doses over periods of 7-10 days in combination with cyclophosphamide and steroids in two patients with haemophilia B and inhibitors. This paper reports similar results in a heamophilia A patient by giving factor VIII, cyclophosphamide, and steroids during relatively short periods of time (7-8 days). The anamnestic response markedly decreased already following the first treatment and never exceeded a level of 1 u/ml (˜ 3 BU/ml) even when boosted with ordinary factor VIII doses for only 3 days. It is concluded that the markedly decreased secondary antibody response is most probably the result of factor VIII given at short intervals (twice a day) for periods of up to about one week when given in combination with cyclophosphamide and steroids. The same effect may be achieved by other methods. The treatment schedule suggested in the present paper is, however, simple and avoids long periods of high antibody levels. Furthermore, the total factor VIII dose used is lower than suggested in most other treatment schedules, which makes the treatment substantially less expensive.

scholarly journals Clinical Use of Factor IX Concentrates

1977 ◽  
Author(s):  
D. Ménaché
Keyword(s):  
Beneficial Effect ◽  
Factor Viii ◽  
Radical Change ◽  
Factor Ix ◽  
Severe Bleeding ◽  
Factor Viii Inhibitor ◽  
Anamnestic Response ◽  
Viii Inhibitor ◽  
Factor Ix Deficiency

The clinical efficacy of Factor IX concentrates in the treatment of patients with Factor IX deficiency is well recognized. The availability of such concentrates has brought a radical change in the management of these patients. The basis for treatment is to obtain an effective Factor IX hemostatic level in vivo. In these conditions, concentrates have been used to reduce the incidence of hemorrhagic episodes in patients particularly exposed and more often to control hemorrhagic episodes or to prevent hemorrhage in the post operative period. Although thromboembolic complications have occured in some instances the major indication of Factor IX concentrates still remains replacement therapy in patients with Factor IX deficiency.More recently Factor IX concentrates have been used for the treatment of patients with antibody to Factor VIII. Although the therapeutic principle(s) responsible for the Factor VIII inhibitor bypassing activity has not yet been characterized several beneficial effect of both “activated” and non activated Factor IX concentrates have been observed in such patients experiencing minor or severe bleeding episodes. On the other hand we are aware of some cases without beneficial effect of Factor IX concentrates in patients with Factor VIII inhibitor. The major complication would seem to be an anamnestic response in some patients resulting in either a moderate or a considerable increase of the Factor VIII inhibitor titer when compared to the initial level before Factor IX concentrates therapy. If Factor IX concentrates prove to be efficacious in the treatment of patients with Factor VIII antibody special attention would be required in the manufacturing processing in order to avoid an anamnestic response.

scholarly journals Incidence of immune responses following 102 infusions of autoplex in 18 hemophilic patients with antibody to factor VIII

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 457-462
Author(s):  
Y Laurian ◽  
JP Girma ◽  
T Lambert ◽  
D Meyer ◽  
MJ Larrieu
Keyword(s):  
Immune Responses ◽  
Factor Viii ◽  
Prothrombin Complex Concentrate ◽  
Hemophilia A ◽  
Significant Rise ◽  
Predisposing Factor ◽  
Anamnestic Response ◽  
Activated Prothrombin Complex Concentrate ◽  
Bleeding Episodes ◽  
High Responders

An activated prothrombin complex concentrate (Autoplex) was infused for the treatment of 102 bleeding episodes in 18 hemophilia A patients with antibody to factor VIII who were previously known as high responders. Among 95 bleeding episodes treated with a single infusion of the concentrate [43–107 factor VIII correcting units (FECU)/kg], only 1 anamnestic response was observed. On the contrary, a significant rise in antibody titer occurred following 2 of 4 double (at 8–12 hr interval) and all 3 multiple (over3 –10 days) infusions of Autoplex. The occurrence of immune responses may be explained by the presence of factor VIII coagulant antigen (VIII:CAg) in the 26 batches of Autoplex tested by two-site immunoradiometric assay (10-–36 U/vial). The anamnestic response was not correlated to the batch used nor to the amount (0.6–7.8 U/kg/day) of VIII:CAg infused per day. However, exposure to the concentrate over several days appeared to be the major predisposing factor for an immune response.

Failure of Immunosuppression in a Severe Haemophilia B Patient with Specific Antibody

1976 ◽  
Vol 36 (01) ◽  
pp. 086-089 ◽  
Author(s):  
Jean-Pierre Allain ◽  
Dominique Frommel
Keyword(s):  
Factor Viii ◽  
Immunosuppressive Therapy ◽  
Specific Antibody ◽  
Factor Ix ◽  
Secondary Response ◽  
Severe Haemophilia ◽  
Anamnestic Response ◽  
Haemophilia B

SummaryPrevention of a secondary response to factor IX by cyclophosphamide was attempted in an 11 year old patient with severe Christmas disease. An antibody to factor IX had been present for 4 years before immunosuppressive therapy was tried. Despite profound lymphopenia, synthesis of factor IX antibody was not depressed. The difficulties of modifying the anamnestic response to factor IX by chemical immunosuppression may be as real as has been reported for factor VIII in classical haemophilia.

Multicenter Retrospective Study on the Utilization of FEIBA in France in Patients with Factor VIII and Factor IX Inhibitors

1997 ◽  
Vol 77 (06) ◽  
pp. 1113-1119 ◽  
Author(s):  
C Negrier ◽  
J Goudemand ◽  
Y Sultan ◽  
M Bertrand ◽  
C Rothschild ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Factor Viii ◽  
Surgical Procedures ◽  
Factor Ix ◽  
Care Providers ◽  
Substitution Product ◽  
Anamnestic Response ◽  
Hiv Seroprevalence ◽  
Bleeding Episodes ◽  
Activated Prothrombin Complex Concentrates

SummaryFactor VIII or factor IX replacement is frequently impossible in inhibitor-developing hemophiliacs, because of the level of the inhibitor titer. Activated prothrombin complex concentrates are one of the available options to treat the bleeding episodes in such patients. However, the efficacy of these products and the associated thrombogenic risk, particularly in prolonged administration such as employed during surgeries, are important concerns for hemophilia care providers. We performed a multicenter retrospective study to evaluate the use of FEIBA (Factor Eight Bypassing Activity) in France, and data is presented on 433 bleeding episodes, including surgical procedures, concerning 60 patients from 15 hemophilia centers.The efficacy was judged as good or excellent in 352 episodes (81.3%), poor in 73 episodes (16.9%) and non-existent in 8 episodes (1.8%). Minor and major surgical procedures were successfully performed using FEIBA as a second-line therapy after human or porcine factor VIII, and in some occasions FEIBA was utilized as the only substitution product. The tolerance was assessed as good in 428 episodes (98.8%), but in 5 cases adverse effects were reported. Only 3 patients out of 52 regularly evaluated (5.8%) were HIV-seropositive, and for two of them the seroconversion occurred prior to the first use of FEIBA. In contrast, 80.4% of the patients were HCV-seropositive. An anamnestic response after the administration of FEIBA was noted in 31.5% of cases. This study points out the main features of the use of FEIBA in France, and particularly the low HIV seroprevalence in the patients treated. The good efficacy and the excellent tolerance still confer to this product a place to consider in the therapeutic options for the treatment of inhibitor-developing hemophiliacs or in acquired hemophilia.

Treatment of Patients with Factor VIII and Factor IX Inhibitors with Special Focus on the Use of Recombinant Factor VIIa

1999 ◽  
Vol 82 (08) ◽  
pp. 531-539 ◽  
Author(s):  
Ulla Hedner
Keyword(s):  
Factor Viii ◽  
Factor Viia ◽  
Immunosuppressive Treatment ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Treatment Modalities ◽  
Special Focus ◽  
Anamnestic Response ◽  
Urgent Surgery ◽  
High Doses

IntroductionIn caring for patients with hemophilia, the development of inhibitors against the missing coagulation protein remains a significant problem. Such inhibitors occur in about 15% of patients with severe hemophilia1 and are directed against the procoagulant part of the factor VIII or factor IX molecules. The goal in the treatment of patients with hemophilia is to achieve high enough levels of the missing factor to induce hemostasis in case of bleeding or to prevent bleeding during surgery. Patients with a low inhibitor titer, and especially those with a low anamnestic response, can be given high doses of the coagulation factor concentrate to induce hemostasis. However, for patients with high inhibitor levels, or high-responders, other treatments must be used, including procedures to decrease the antibody titers. To minimize the booster effect of high doses of antigen, immunosuppressive treatment may be added. Because such treatment procedures are complicated and associated with a number of potential side effects, they are not often used to treat mild-to-moderate bleeding episodes or to cover elective, less urgent surgery for inhibitor patients. As a result, a great deal of effort has been devoted to finding more convenient treatment modalities and to inducing immunologic tolerance to permanently eradicate the inhibitors.

TOLERANCE INDUCTION IN HIGH-RESPONDING HEMOPHILIACS WITH F VIII ANTIBODIES BY MEANS OF COMBINED TREATMENT WITH IgG, CYCLOPHOSPHAMIDE AND F VIII

1987 ◽  
Author(s):  
I M Nilsson ◽  
E Berntorp ◽  
O Zettervall
Keyword(s):  
Hemophilia A ◽  
Combined Treatment ◽  
Protein A ◽  
Tolerance Induction ◽  
Antibody Concentration ◽  
High Dose ◽  
Anamnestic Response ◽  
High Concentrations ◽  
High Responders ◽  
Tolerant State

Of 10 patients with hemophilia A and antibodies, 7 have been rendered tolerant by means of combined treatment with high-dose IgG i.v., cyclophosphamide and F VIII. When the initial antibody concentration exceeded 10 Bethesda inhibitor units per ml, the treatment was preceded by antibody adsorption to protein A. Six of the tolerant patients were originally classified as high-responders. After one week of the combined treatment, VI11:C dropped and the inhibitor reappeared in low titer. The F VIII infusions being continued alone, the inhibitor disappeared in the following week and VIII:C increased satisfactorily after infusion, while VIII:Ag (assayed immunoradiometrically) reached very high concentrations. In one patient the treatment had to be repeated once. Except for transient leukopenia, no side effects occurred. Earlier treatments with F VIII in combination with cyclophosphamide gave high anamnestic response. In two of the remaining three non-tolerant patients, anamnestic response decreased dramatically after two courses of the combined treatment. The tolerant state seems to be stable, as the tolerant patients have now been on regular prophylaxis with F VIII concentrate for periods varying from four months to four years. The half-life of infused F VIII is normal, while that of VIII:Ag is prolonged. On the basis of similar findings in hemophilia B patients, we believe the VIII:Ag to have become modi Tied and complexed to a 'new' antibody which lacks VIII:C inhibitory activity. It is known that modified antigen may act as a tolerogen. The tolerant state may thus be sustained by maintaining consistent concentrations of the modified antigen by means of the F VIII treatment. We conclude that the combined treatment described here is a safe and effective method of tolerance induction in hemophilia A patients.

scholarly journals Incidence of immune responses following 102 infusions of autoplex in 18 hemophilic patients with antibody to factor VIII

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 457-462 ◽  
Author(s):  
Y Laurian ◽  
JP Girma ◽  
T Lambert ◽  
D Meyer ◽  
MJ Larrieu
Keyword(s):  
Immune Responses ◽  
Factor Viii ◽  
Prothrombin Complex Concentrate ◽  
Hemophilia A ◽  
Significant Rise ◽  
Predisposing Factor ◽  
Anamnestic Response ◽  
Activated Prothrombin Complex Concentrate ◽  
Bleeding Episodes ◽  
High Responders

Abstract An activated prothrombin complex concentrate (Autoplex) was infused for the treatment of 102 bleeding episodes in 18 hemophilia A patients with antibody to factor VIII who were previously known as high responders. Among 95 bleeding episodes treated with a single infusion of the concentrate [43–107 factor VIII correcting units (FECU)/kg], only 1 anamnestic response was observed. On the contrary, a significant rise in antibody titer occurred following 2 of 4 double (at 8–12 hr interval) and all 3 multiple (over3 –10 days) infusions of Autoplex. The occurrence of immune responses may be explained by the presence of factor VIII coagulant antigen (VIII:CAg) in the 26 batches of Autoplex tested by two-site immunoradiometric assay (10-–36 U/vial). The anamnestic response was not correlated to the batch used nor to the amount (0.6–7.8 U/kg/day) of VIII:CAg infused per day. However, exposure to the concentrate over several days appeared to be the major predisposing factor for an immune response.

Management of Haemophilia in Sweden

1976 ◽  
Vol 35 (03) ◽  
pp. 510-521 ◽  
Author(s):  
Inga Marie Nilsson
Keyword(s):  
Factor Viii ◽  
Total Population ◽  
Age Groups ◽  
Factor Ix ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Haemophilia B ◽  
Human Fraction ◽  
Mild Haemophilia

SummaryThe incidence of living haemophiliacs in Sweden (total population 8.1 millions) is about 1:15,000 males and about 1:30,000 of the entire population. The number of haemophiliacs born in Sweden in 5-year periods between 1931-1975 (June) has remained almost unchanged. The total number of haemophilia families in Sweden is 284 (77% haemophilia A, 23% haemophilia B) with altogether 557 (436 with A and 121 with B) living haemophiliacs. Of the haemophilia A patients 40 % have severe, 18 % moderate, and 42 % mild, haemophilia. The distribution of the haemophilia B patients is about the same. Inhibitors have been demonstrated in 8% of the patients with severe haemophilia A and in 10% of those with severe haemophilia B.There are 2 main Haemophilia Centres (Stockholm, Malmo) to which haemophiliacs from the whole of Sweden are admitted for diagnosis, follow-up and treatment for severe bleedings, joint defects and surgery. Minor bleedings are treated at local hospitals in cooperation with the Haemophilia Centres. The concentrates available for treatment in haemophilia A are human fraction 1-0 (AHF-Kabi), cryoprecipitate, Antihaemophilic Factor (Hyland 4) and Kryobulin (Immuno, Wien). AHF-Kabi is the most commonly used preparation. The concentrates available for treatment in haemophilia B are Preconativ (Kabi) and Prothromplex (Immuno). Sufficient amounts of concentrates are available. In Sweden 3.2 million units of factor VIII and 1.0 million units of factor IX are given per year. Treatment is free of charge.Only 5 patients receive domiciliary treatment, but since 1958 we in Sweden have practised prophylactic treatment of boys (4–18 years old) with severe haemophilia A. At about 5-10 days interval they receive AHF in amounts sufficient to raise the AHF level to 40–50%. This regimen has reduced severe haemophilia to moderate. The joint score is identical with that found in moderate haemophilia in the same age groups. For treatment of patients with haemophilia A and haemophilia B complicated by inhibitors we have used a large dose of antigen (factor VIII or factor IX) combined with cyclophosphamide. In most cases this treatment produced satisfactory haemostasis for 5 to 30 days and prevented the secondary antibody rise.

The Effect of Adrenaline Infusions on Blood Coagulation in Normal and Haemophilia B Dogs

1966 ◽  
Vol 15 (03/04) ◽  
pp. 349-364 ◽  
Author(s):  
A.H Özge ◽  
H.C Rowsell ◽  
H.G Downie ◽  
J.F Mustard
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Factor Ix ◽  
Clotting Factor ◽  
Blood Ph ◽  
Order Of Magnitude ◽  
Dose Dependent ◽  
Generation Test ◽  
Plasma Activity

SummaryThe addition of trace amounts of adrenaline to whole blood in plasma in vitro increased factor VIII, factor IX and whole plasma activity in the thromboplastin generation test. This was dose dependent.Adrenaline infusions less than 22 (μg/kg body weight in normal dogs accelerated clotting, increased factor IX, factor VIII and whole plasma activity in the thromboplastin generation test and caused a fall in blood pH. In a factor IX deficient dog, there was no increase in factor IX activity. After adrenaline infusions, however, the other changes occurred and were of the same order of magnitude as in the normal. Adrenaline in doses greater than 22 μg/kg body weight did not produce as great an effect on clotting in normal or factor IX deficient dogs. The platelet count in the peripheral blood was increased following the infusion of all doses of adrenaline. These observations suggest that the accelerating effect of adrenaline on clotting is not mediated through increase in activity of a specific clotting factor.

A Survey of the Effectiveness of Prothrombin Complex Concentrates in Controlling Hemorrhage in Patients with Hemophilia and Anti-Factor VIII Antibodies

1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts
Keyword(s):  
Factor Viii ◽  
Ad Hoc ◽  
Hemophilia A ◽  
Working Party ◽  
International Committee ◽  
Factor Ix ◽  
Prothrombin Complex Concentrates ◽  
Factor Viii Concentrates

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

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