EDITOR'S COLUMN
Treatment of hemophilic children who have factor VIII inhibitors
THE DEVELOPMENT Of stable, concentrated preparations of coagulation factors has revolutionized the care and dramatically improved the quality of life for hemophilic children. These concentrates have permitted prompt and effective replacement therapy, often administered at home by the patient or his family. It is likely that many of the present generation of hemophilic children will attain adulthood without the physical and psychologic crippling nearly universal in the past. This promise is shattered in about 10% of patients with EXTRINSIC SYSTEM
INTRINSIC SYSTEM
Tissue Thromboplastin
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FIBRIN
Fig. 1. Schematic representation of the coagulation mechanism. The activated factors, indicated with an asterisk, interact in the cascade distal to the level of factor VIII, bypassing the effects of inhibitors.
classical hemophilia by the development of circulating factor VIII inhibitors. These inhibitors, gamma globulins with the characteristics of antibody, effectively neutralize the coagulant activity of infused factor VIII and prevent effective therapy. Administration of massive amounts of factor VIII concentrates in some instances may overwhelm the inhibitors and temporarily attain hemostasis; but in many patients, very high titers of antibody preclude correction. The staggering expense of the large amounts of concentrates necessary to overcome even low-titer inhibitors deters therapy of bleeding episodes unless they are life threatening. The frequent incapacitating, crippling, and painful "minor bleeds" must be managed by symptomatic and often ineffective therapies including wrapping, splinting, ice packing, and analgesia so poignantly and accurately described by Robert and Suzanne Massie, themselves the parents of a hemophiliac child, in their books Nicholas and A lexandra and Journey. See related articles, pp. 200 and 356.
Recently, an ingenious new approach to the treatment of the hemophilic patient with a circulating inhibitor has been described. A number of coagulation factors, especially factors VII, X, and II, interact in the coagulation cascade distal to the level of action of factor VIII. Commercial preparations (Konyne, Proplex) apparently may contain small amounts of these factors in an activated form. When these are added to plasma, they appear to effectively bypass the effects of factor VIII inhibitors (Fig. 1). Administration of these preparations to hemophilic patients with factor VIII inhibitors has been reported to effectively control a substantial number of severe bleeding episodes. The papers by Abilgaard and associates and Goodnight and associates in this issue convincingly document the effectiveness of this form of therapy in hemophilic children. This approach must still be considered investigational. More work is necessary to define the precise basis of action, the best therapeutic preparations,
The Journal of P E D I A T R I C S Vol. 88, No. 2. pp. 367-368
367
368
Editor's column
and the most effective dosages and schedules. There are real and potential dangers of such therapy including the heavy contamination of some preparations with the hepatitis B virus and the risk of thrombosis as a result of hypercoagulability. Nevertheless, the increasing number of reports of successful treatment of this disastrous complication raises high hope that these hemophilic
The Journal of Pediatrics February 1976
children can again be treated effectively and returned to a useful and comfortable coexistence with their disease. Howard A. Pearson, M.D. Department o f Pediatrics Yale University School o f Medicine 333 Cedar St. New Haven, Conn. 06510
Treatment of hemophilic children who have factor VIII inhibitors
THE DEVELOPMENT Of stable, concentrated preparations of coagulation factors has revolutionized the care and dramatically improved the quality of life for hemophilic children. These concentrates have permitted prompt and effective replacement therapy, often administered at home by the patient or his family. It is likely that many of the present generation of hemophilic children will attain adulthood without the physical and psychologic crippling nearly universal in the past. This promise is shattered in about 10% of patients with EXTRINSIC SYSTEM
INTRINSIC SYSTEM
Tissue Thromboplastin
~XTT (Hageman
FactorI /
(PTA)
/
J
IX (Christmas
Factor) J
(Antihemophilic Factor
~]IT.a*
>
/
u
/
/ H
I
(Fibrinogenl
XTTa
>
~'Ta
>
IXa
"~IIIQ
j
AHF)
X
(Prothrombin)
/
)
)
Xa*
>
7a
>
TTa*
l
(Yhrombin) )
FIBRIN
Fig. 1. Schematic representation of the coagulation mechanism. The activated factors, indicated with an asterisk, interact in the cascade distal to the level of factor VIII, bypassing the effects of inhibitors.
classical hemophilia by the development of circulating factor VIII inhibitors. These inhibitors, gamma globulins with the characteristics of antibody, effectively neutralize the coagulant activity of infused factor VIII and prevent effective therapy. Administration of massive amounts of factor VIII concentrates in some instances may overwhelm the inhibitors and temporarily attain hemostasis; but in many patients, very high titers of antibody preclude correction. The staggering expense of the large amounts of concentrates necessary to overcome even low-titer inhibitors deters therapy of bleeding episodes unless they are life threatening. The frequent incapacitating, crippling, and painful "minor bleeds" must be managed by symptomatic and often ineffective therapies including wrapping, splinting, ice packing, and analgesia so poignantly and accurately described by Robert and Suzanne Massie, themselves the parents of a hemophiliac child, in their books Nicholas and A lexandra and Journey. See related articles, pp. 200 and 356.
Recently, an ingenious new approach to the treatment of the hemophilic patient with a circulating inhibitor has been described. A number of coagulation factors, especially factors VII, X, and II, interact in the coagulation cascade distal to the level of action of factor VIII. Commercial preparations (Konyne, Proplex) apparently may contain small amounts of these factors in an activated form. When these are added to plasma, they appear to effectively bypass the effects of factor VIII inhibitors (Fig. 1). Administration of these preparations to hemophilic patients with factor VIII inhibitors has been reported to effectively control a substantial number of severe bleeding episodes. The papers by Abilgaard and associates and Goodnight and associates in this issue convincingly document the effectiveness of this form of therapy in hemophilic children. This approach must still be considered investigational. More work is necessary to define the precise basis of action, the best therapeutic preparations,
The Journal of P E D I A T R I C S Vol. 88, No. 2. pp. 367-368
367
368
Editor's column
and the most effective dosages and schedules. There are real and potential dangers of such therapy including the heavy contamination of some preparations with the hepatitis B virus and the risk of thrombosis as a result of hypercoagulability. Nevertheless, the increasing number of reports of successful treatment of this disastrous complication raises high hope that these hemophilic
The Journal of Pediatrics February 1976
children can again be treated effectively and returned to a useful and comfortable coexistence with their disease. Howard A. Pearson, M.D. Department o f Pediatrics Yale University School o f Medicine 333 Cedar St. New Haven, Conn. 06510
