Investigations on Hemophilia

Abstract

Three years ago one of us1 reported on clinical and experimental investigations on two children with hemophilia and summarized the current ideas as to the cause of the abnormally prolonged coagulation time in that disease. Also, some experiments were reported regarding the existence of a substance promoting coagulation which should be present in normal plasma and serum and almost absent from the plasma and serum of patients with hemophilia. These experiments were based on the finding of Govaerts and Gratia,2 which was confirmed and amplified, that normal plasma and serum when totally free from the coagulation ferment are able to accelerate coagulation, even in small concentration. Ultrafiltrates of normal plasma or serum do not have this influence. The substance which might be held responsible for the coagulation-promoting influence has been examined more closely. This article contains the results of the investigation and also those of the first clinical applications. CHEMICAL STUDIESTo which protein fraction of the serum or the plasma does the coagulation-promoting substance show the greatest affinity?One of us J found that the coagulation-promoting substance present in normal plasma and serum not only was nonultrafiltrable but was absent from the so-called protein-containing ultrafiltrate, i. e., an ultra¬ filtrate obtained by using a membrane with increased permeability.1 Probably in agreement with this result is the fact that the coagulationpromoting substance was also found to be absent from ascites fluid. From these facts it was concluded that the coagulation-promoting sub¬ stance must be present in the coarse-disperse protein fractions of the plasma.

Van Creveld, pioneer of hemophilia care and coagulation research in the Netherlands: a personal account

“…Nevertheless, it seems justifiable to conclude that Van Creveld and his coworkers were among the first to discover AHF. According to Van Creveld this was not a matter of debate: ÔWith pleasure we mention the fact that this part of our research work, as well as our results obtained by application in vivo, has since then been fully confirmed by the investigations of Patek and TaylorÕ [9]. And: ÔThese results (described in [6,7]) were confirmed by the work of Patek and Taylor and of Patek and Stetson.…”

“…The provisional results justify a continuation of the research in this directionÕ [7]. In a subsequent series of papers published at relatively short intervals, again in Acta Brevia Neerlandica, Van Creveld and his coworker Bendien and later Mastenbroek and Paulssen documented more clearly the fact that from both biochemical and clinical points of view their Ôcoagulation-globulinÕ, later known as antihemophilic factor (AHF), indeed contained the active principle lacking in hemophilia [8][9][10][11][12][13][14][15]. The interpretation of their data was somewhat clouded, because at the beginning of their studies it was not entirely clear whether they used serum or plasma as the starting material for their experiments.…”

The initial stages of blood coagulation

“…Generation could be proportionately restored by adding increasing amounts of normal plasma or its fibrinogen fraction to the haemophilic plasma, suggesting that the inactivity of the latter was due to the absence of a normal factor rather than the presence of an inhibitor (Biggs & Douglas, 1953). From this it can be concluded that the factor known as 'anti-haemophilic globulin' is required for thromboplastin generation since this factor is associated with the fibrinogen fraction of normal blood and is deficient in haemophilia (Bendien & van Creveld, 1937;Pohle & Taylor, 1937;Minot & Taylor, 1947).…”

Studies of Hemophilia. Ii. The Assay of the Antihemophilic Clot-Promoting Principle in Normal Human Plasma With Some Observations on the Relative Potency of Certain Plasma Fractions 1

“…Re-precipitation with CO2 resulted in large losses of antihemophilic potency. 4 Obtained through the courtesy of Dr. John T. Edsall, Dept. of Physical Chemistry, Harvard Medical School, from the Mass.…”