- Email: [email protected]
ORAL TREATMENT OF HAEMOPHILIA A BY FACTOR VIII BOUND TO CHYLOMICRA
1310
Letters to the Editor ORAL TREATMENT OF HAEMOPHILIA A BY FACTOR VIII BOUND TO CHYLOMICRA
SIR,-Hemker et al.l have demonstrated that oral administration factor-VIII-loaded
liposomes can raise plasma FVIII Oral administration of FVIII preparations would be more convenient than intravenous administration. FVIII can be purified from cryoprecipitate by gel chromatography on agarose.2We observedthat both FVIII and chylomicra were present in the exclusion volume of the agarose column. Moreover, both in these preparations and in lymph, FVIII is bound to chylomicra.3Encouraged by the observations of Hemker et al. we have been testing oral administration of chylomicron bound FVIII. A 22-month-old boy was admitted to hospital with a history of recurrent epistaxis and bruising. His maternal grandfather and four cousins have haemophilia. His plasma FVIII activity was 8-10% of normal and FVIII related antigen was 0 -88 U/ml: thus he had mild haemophilia A. For 8 months human FVIII was given orally twice a week, with a one month break halfway. At the end of this period, the preparation was administered daily for 4 consecutive days. FVIII procoagulant activity was measured immediately before and 24 hours after ingestion. FVIII loaded chylomicra were prepared on a 80 x 5 cm agarose bead column (’Sepharose 6B’; Pharmacia Fine Chemicals, Uppsala) with 13 mmol/1 trisodium citrate and 0-14 mol/1 sodium chloride in sterile water as elution fluid. Some 60 ml of fresh frozen human cryoprecipitate from four donors was run on the column, the FVIII activity bound to chylomicra being in the exclusion volume. The concentration of FVIII procoagulant activity in the preparation varied from 100 to 150 units, in volumes of about 80 ml. Plasma FVIII concentration rose from 9% of normal to 15%, 3 h after a single dose, and at 6 h and 24 h values were 13% and 14%, of
procoagulant activity.
Daily administration of this oral preparation achieved FVIII concentrations sufficient for prophylaxis and treatment of minor bleeds. FVIII was demonstrable in the patient’s plasma for longer than would be expected from the half-life of FVIII in blood, suggesting the presence of a depot from which .the orally administered FVIII can enter the plasma. This conclusion accords with that of Hemker et al.We now need more experience, in adults and in patients with severe haemophilia. Departments of Clinical Biochemistry and Paediatrics, St Clara Hospital, Rotterdam, Netherlands
M. M. P. PAULSSEN B. C. VAN PELT
FRESH FROZEN PLASMA FOR VASO-OCCLUSIVE CRISES IN SICKLE CELL DISEASE
SIR,-In 1980 Hebbel et al.’ reported that the red cells of patients with sickle cell anaemia adhered to cultured endothelial cells in vitro, whereas normal red cells did not. Cells of severely affected patients adhered more than did those of the mildly affected individuals. Stuart and her colleagues2showed that patients with sickle cell disease have decreased plasma prostacyclin (PGI2) regenerative capacity and that this returns to normal after exchange transfusion. In thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, the ability of plasma to stimulate the release of PGI2 or PG,2-like activity from vascular tissues is reduced.3-6 This defect can be corrected in some patients by the infusion of fresh frozen plasma (FFP),5 or by plasma exchange.6 We have given FFP, as part of our standard rehydration regimen, to patients with sickle cell disease who are having a painful crisis, in the hope that it may shorten or ameliorate the crisis. Seventeen vaso-occlusive (painful) crises in eleven patients have been treated in this manner since December, 1980. The details of the patients are shown in the table. Two units of FFP were given to
respectively. After this single dose experiment we decided to adminster human FVIII twice weekly with intervals of 3 and 4 days. Over an 8 month period an emulsion containing 100-150 units of FVIII was administered 75 times. The lowest FVIII concentrations ranged from 12% (4 days after a dose) to 22% (1day after administration). When treatment was stopped for a month the FVIII level dropped to 8-10%. Subsequently, the effects of daily administration were investigated: FVIII concentrations have varied between 20 and 30%, 24 h after ingestion (see table). No circulating anticoagulants
DETAILS OF PATIENTS STUDIED
have been demonstrated.
1.
Hemker HC, Hermens WTH, Muller AD, Zwaal RFA. Oral treatment of haemophilia A by gastrointestinal adsorption offactor-VIII entrapped in liposomes. Lancet 1980
i: 70-71. 2 Paulssen MMP, Wouterlood ACMGB, Scheffers HLMA. Purification of the antihemophilic factor by gel filtration on agarose Thromb Diath Haemorrh 1969; 22: 577-83 3. Paulssen MMP, Vandenbussche-Scheffers HLMA, Spaan PB, de Jong T, Planje MC Studies on the characterization of factor-VIII and co-factor-VIII. Thromb Diath Haemorrh 1974; 31: 328-38.
*From
September, 1979,
to
March, 1981.
tChest syndrome. adults and one to children as part of the rehydration regimen either admission (fourteen crises) or 72 h later (three crises). In fifteen of these crises patients experienced an immediate subjective improvement in well-being and the relief of pain. The patients are on
FVIII ACTIVITY IN PLASMA AFTER DAILY ADMINISTRATION OF FVIII
ORALLY FOR FOUR CONSECUTIVE DAYS
(NOV. 17-20)
,
1. Hebbel RP, Boogaerts MAB, Eaton JW, Steinberg MH. Erythrocyte adherence to endothelium in sickle cell anemia. N EnglJ Med 1980; 302: 992-95. 2. Stuart MJ, Blinder E, Sills R. Abnormal vascular Prostaglandin I2 (PGI2) synthesis in sickle cell anaemia. 18th meeting of International Society of Haematology (Montreal, August, 1980): abstr. 1612. 3. Remuzzi G, Misiani R, Marchesi P, Livio M, Mecca G, De Gaetano G, Donati M 4.
4.
I
I
I
*Plasma activity determined before each dose (i.e., 24 h aftr the previous dose) 1. and on Nov. 21.
Haemolytic uraemic syndrome: Deficiency of plasma factors regulating prostacycline activity Lancet 1978; ii: 871-72. Brandt JT, Kennedy MS, Seuhauser D. Platelet aggregation factor in thrombotic thrombocytopenic purpura. Lancet 1979; ii. 463- 64
5. Remuzzi G, Misiani R, Marchesi P, Livio M, Mecca G, De Gaetano G, Donati M Treatment of haemolytic uraemic syndrome with plasma. Clin Nephrol 1979, 12: 279-84. 6. Machin SJ, Defreyn G, Chamone DAF, Vermylen J. Plasma 6-keto PGF 1&agr; levels after plasma exchange in thrombotic thrombocytopenic purpura Lancet 1980; i 661
Letters to the Editor ORAL TREATMENT OF HAEMOPHILIA A BY FACTOR VIII BOUND TO CHYLOMICRA
SIR,-Hemker et al.l have demonstrated that oral administration factor-VIII-loaded
liposomes can raise plasma FVIII Oral administration of FVIII preparations would be more convenient than intravenous administration. FVIII can be purified from cryoprecipitate by gel chromatography on agarose.2We observedthat both FVIII and chylomicra were present in the exclusion volume of the agarose column. Moreover, both in these preparations and in lymph, FVIII is bound to chylomicra.3Encouraged by the observations of Hemker et al. we have been testing oral administration of chylomicron bound FVIII. A 22-month-old boy was admitted to hospital with a history of recurrent epistaxis and bruising. His maternal grandfather and four cousins have haemophilia. His plasma FVIII activity was 8-10% of normal and FVIII related antigen was 0 -88 U/ml: thus he had mild haemophilia A. For 8 months human FVIII was given orally twice a week, with a one month break halfway. At the end of this period, the preparation was administered daily for 4 consecutive days. FVIII procoagulant activity was measured immediately before and 24 hours after ingestion. FVIII loaded chylomicra were prepared on a 80 x 5 cm agarose bead column (’Sepharose 6B’; Pharmacia Fine Chemicals, Uppsala) with 13 mmol/1 trisodium citrate and 0-14 mol/1 sodium chloride in sterile water as elution fluid. Some 60 ml of fresh frozen human cryoprecipitate from four donors was run on the column, the FVIII activity bound to chylomicra being in the exclusion volume. The concentration of FVIII procoagulant activity in the preparation varied from 100 to 150 units, in volumes of about 80 ml. Plasma FVIII concentration rose from 9% of normal to 15%, 3 h after a single dose, and at 6 h and 24 h values were 13% and 14%, of
procoagulant activity.
Daily administration of this oral preparation achieved FVIII concentrations sufficient for prophylaxis and treatment of minor bleeds. FVIII was demonstrable in the patient’s plasma for longer than would be expected from the half-life of FVIII in blood, suggesting the presence of a depot from which .the orally administered FVIII can enter the plasma. This conclusion accords with that of Hemker et al.We now need more experience, in adults and in patients with severe haemophilia. Departments of Clinical Biochemistry and Paediatrics, St Clara Hospital, Rotterdam, Netherlands
M. M. P. PAULSSEN B. C. VAN PELT
FRESH FROZEN PLASMA FOR VASO-OCCLUSIVE CRISES IN SICKLE CELL DISEASE
SIR,-In 1980 Hebbel et al.’ reported that the red cells of patients with sickle cell anaemia adhered to cultured endothelial cells in vitro, whereas normal red cells did not. Cells of severely affected patients adhered more than did those of the mildly affected individuals. Stuart and her colleagues2showed that patients with sickle cell disease have decreased plasma prostacyclin (PGI2) regenerative capacity and that this returns to normal after exchange transfusion. In thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, the ability of plasma to stimulate the release of PGI2 or PG,2-like activity from vascular tissues is reduced.3-6 This defect can be corrected in some patients by the infusion of fresh frozen plasma (FFP),5 or by plasma exchange.6 We have given FFP, as part of our standard rehydration regimen, to patients with sickle cell disease who are having a painful crisis, in the hope that it may shorten or ameliorate the crisis. Seventeen vaso-occlusive (painful) crises in eleven patients have been treated in this manner since December, 1980. The details of the patients are shown in the table. Two units of FFP were given to
respectively. After this single dose experiment we decided to adminster human FVIII twice weekly with intervals of 3 and 4 days. Over an 8 month period an emulsion containing 100-150 units of FVIII was administered 75 times. The lowest FVIII concentrations ranged from 12% (4 days after a dose) to 22% (1day after administration). When treatment was stopped for a month the FVIII level dropped to 8-10%. Subsequently, the effects of daily administration were investigated: FVIII concentrations have varied between 20 and 30%, 24 h after ingestion (see table). No circulating anticoagulants
DETAILS OF PATIENTS STUDIED
have been demonstrated.
1.
Hemker HC, Hermens WTH, Muller AD, Zwaal RFA. Oral treatment of haemophilia A by gastrointestinal adsorption offactor-VIII entrapped in liposomes. Lancet 1980
i: 70-71. 2 Paulssen MMP, Wouterlood ACMGB, Scheffers HLMA. Purification of the antihemophilic factor by gel filtration on agarose Thromb Diath Haemorrh 1969; 22: 577-83 3. Paulssen MMP, Vandenbussche-Scheffers HLMA, Spaan PB, de Jong T, Planje MC Studies on the characterization of factor-VIII and co-factor-VIII. Thromb Diath Haemorrh 1974; 31: 328-38.
*From
September, 1979,
to
March, 1981.
tChest syndrome. adults and one to children as part of the rehydration regimen either admission (fourteen crises) or 72 h later (three crises). In fifteen of these crises patients experienced an immediate subjective improvement in well-being and the relief of pain. The patients are on
FVIII ACTIVITY IN PLASMA AFTER DAILY ADMINISTRATION OF FVIII
ORALLY FOR FOUR CONSECUTIVE DAYS
(NOV. 17-20)
,
1. Hebbel RP, Boogaerts MAB, Eaton JW, Steinberg MH. Erythrocyte adherence to endothelium in sickle cell anemia. N EnglJ Med 1980; 302: 992-95. 2. Stuart MJ, Blinder E, Sills R. Abnormal vascular Prostaglandin I2 (PGI2) synthesis in sickle cell anaemia. 18th meeting of International Society of Haematology (Montreal, August, 1980): abstr. 1612. 3. Remuzzi G, Misiani R, Marchesi P, Livio M, Mecca G, De Gaetano G, Donati M 4.
4.
I
I
I
*Plasma activity determined before each dose (i.e., 24 h aftr the previous dose) 1. and on Nov. 21.
Haemolytic uraemic syndrome: Deficiency of plasma factors regulating prostacycline activity Lancet 1978; ii: 871-72. Brandt JT, Kennedy MS, Seuhauser D. Platelet aggregation factor in thrombotic thrombocytopenic purpura. Lancet 1979; ii. 463- 64
5. Remuzzi G, Misiani R, Marchesi P, Livio M, Mecca G, De Gaetano G, Donati M Treatment of haemolytic uraemic syndrome with plasma. Clin Nephrol 1979, 12: 279-84. 6. Machin SJ, Defreyn G, Chamone DAF, Vermylen J. Plasma 6-keto PGF 1&agr; levels after plasma exchange in thrombotic thrombocytopenic purpura Lancet 1980; i 661