Toxicity of Heparinoids, with Special Reference to the Precipitation of Fibrinogen^[*]

Summary

To demonstrate whether the intravascular precipitation of fibrinogen is responsible for the toxicity of heparinoid, the relation between the toxicity of heparinoid in vivo and the precipitation of fibrinogen in vitro was investigated, using dextran sulfate of various molecular weights and various heparinoids.

1. There are close relationships between the molecular weight of dextran sulfate, its toxicity, and the quantity of fibrinogen precipitated.

2. The close relationship between the toxicity and the precipitation of fibrinogen found for dextran sulfate holds good for other heparinoids regardless of their molecular structures.

3. Histological findings suggest strongly that the pathological changes produced with dextran sulfate are caused primarily by the intravascular precipitates with occlusion of the capillaries.

From these facts, it is concluded that the precipitates of fibrinogen with heparinoid may be the cause or at least the major cause of the toxicity of heparinoid.

4. The most suitable molecular weight of dextran sulfate for clinical use was found to be 5,300 ~ 6,700, from the maximum value of the product (LD₅₀ · Anticoagulant activity). This product (LD₅₀ · Anticoagulant activity) can be employed generally to assess the comparative merits of various heparinoids.

5. Clinical use of the dextran sulfate prepared on this basis gave satisfactory results. No severe reaction was observed. However, two delayed reactions, alopecia and thrombocytopenia, were observed. These two reactions seem to come from the cause other than intravascular precipitation.

^* Part of this work was presented before the 20th General Meeting of the Japanese Hematological Society at Nagoya, Japan, March 28, 1958, and the 6th Annual Meeting of the Canadian Federation of Biological Societies at London, Ontario, Canada, June 19, 1963.

^** Research Fellow, Medical Research Council, Canada. Present address of Dr. Sasaki is Department of Physiology, Nagoya University School of Medicine, Showa-ku, Nagoya, Japan.

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