Chapter XV 

 THE FUNCTION OF HEPARIN 



Peptone shock in the dog 



THE feeling of uneasiness regarding the alleged function of heparin in 

 the body, mentioned in the introduction, became even more acute 

 as the present work progressed. 



The histological investigations on the distribution of the mast cells in various 

 species and on the relationship of the mast cells to the small blood vessels, 

 studied in detail in the ox and rat, left little doubt that tissue mast cells secrete 

 their metachromatic substance not directly into the blood, but into the tissue 

 spaces and thence by the lymphatics to reach the blood, if at all, by a circuitous 

 route. Heparin (or heparin combined with its albumin co-factor) is too big 

 a molecule to re-enter the venous capillary circulation; applied direct to the 

 capillary wall, heparin lodges in the interendothelial cement (Macintosh, 

 Ciba Symp. 1956, p. 407). It was clear, even at this point, that the earlier 

 hypothesis could hardly be correct. There is no easy entry for heparin into the 

 blood in most species. The function of heparin must lie in the tissues. 



However, there still remain unexplained the phenomena of peptone and 

 anaphylactic shock in the dog, in which it is certain that heparin and histamine do 

 reach the general circulation, and that the massive release of both occurs mainly 

 in the liver (Wilander, 1938; Rocha e Silva et a/, 1947; Jaques et al, 1954). 



In earlier (unpublished) work I was impressed by the consistent, though 

 slight, differences in time sequence of the histamine and heparin peaks in the 

 blood in peptone shock : this step-wise release, first of histamine which causes 

 the 'shock' and, second, of heparin which causes the incoagulability, at first 

 sight appears to weigh seriously against a common origin for the two substances. 

 Yet logical extension of the knowledge which we have gained of tissue mast cells 

 in general, to the special case of the shocked dog, suggests an interesting and 

 plausible explanation why histamine and heparin must be 'out of phase' in 

 their entry into the peripheral blood: for if heparin in the tissues is drained 

 (if it is drained at all) by way of the lymphatics, then heparin from the liver will 

 be drained in similar fashion; and the main efferent lymphatic pathway from 

 the liver to the blood is the thoracic duct. Here the pathway is direct. 



Thus we may picture the peptone acting on the mast cells in the liver of the 

 dog : this explains the few seconds' delay between the moment of injection of 

 the peptone and the onset of the shock. It is the characteristic delay of a 

 histamine-liberator seeking its target, the mast cells. However, at this point 

 the routes of the two components of the mast cells diverge : histamine enters 



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