Changes in Pulmonary Vascular Resistance due to Platelet Aggregation; Vasoconstriction or Vascular Obstruction?

Beitr. Path. Bd. 152,99-104 (1974)

Review

Institute of Experimental Therapy and Institute of Pathology of the University of Freiburg/W. Germany

Changes in Pulmonary Vascular Resistance due to Platelet Aggregation; Vasoconstriction or Vascular Obstruction? Veranderungen des pulmonalen GefaBwiderstandes durch Plattchenaggregation: Vasokonstriktion oder GefaBverschluB? K. A. SCHUMACHER and CH. MITTERMAYER Received Januar 23 , 1974 . Accepted February 7, 1974

Massive platelet aggregation is known to induce considerable reactions of total circulation, the predominant effect being an incre,!-se in pulmonary vascular resistance (PVR). Aggregates appearing as microemboli in terminal lung vessels in severe shock of different origin are of special interest, and are thought to be aetiologically associated with the appearance of shock symptoms (HARDAWAY, 1962; ROBB, 1963; ROBB et aI., 1972; ALLARDYCE, 1969; MITTERMAYER et aI., 1970). The increase in PVR is often believed to be the result of simple obstruction of pulmonary circulation owing to platelet aggregation. However, pulmonary circulation in shock is an unsuitable experimental model to obtain definite evidence for this hypothesis, since the causes of both the appearance of microemboli and the circulatory changes are various and,d ifficult to determine. For this reason, some investigators studied the changes in PVR associated with massive platelet aggregation. The following factors may be of aetiological importance: After reaching a certain particle size, platelet aggregates cause obstruction of terminal lung vessels and thus multiple microembolisation, or induce the release of platelet components. Among them, especially 5-hydroxytryptamine (5-HT) may raise PVR as a result of its vasoactivity. Whether the increase in PVR in cases of massive platelet aggregation is due to obstruction, vasoconstriction or to both of these factors, remains to be elucidated. 7 Beitr. Path. Bd. 152

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Morphological and pharmacological studies are being performed to settle this question. Although morphological investigations permit a semiquantitative assessment of the obstruction of terminal lung vessels by platelet clumping, some authors believe that these methods do not provide conclusive evidence, since the haemodynamic effects of the obstruction and the influence of a vasoactive component cannot be evaluated. On the other hand, even the selection of an aggregation-inducing compound suitable for pharmacological studies poses a difficult problem, since this substance is expected to cause an acute, massive, pure platelet aggregation (regardless of any possible inclusion of leucocytes), without provoking release reactions. Furthermore, it should not have any vasoactivity of its own and it should not produce endothelial damage or intravascular coagulation. As a matter of fact, there is no compound that fulfils all these requirements. The effects of adenosine diphosphate (ADP) and 5-hydroxytryptamine (5-HT) are of particular interest. In vivo, both compounds induce platelet aggregation and influence PVR. As platelet components, they may act upon thrombocytes and blood vessels after their release, e.g. via the collagen, thrombin or antigen-antibody complexes, but also by an indirect mechanism. ADP-induced platelet aggregates are temporarily held in the terminal lung vessels. Histological evidence has been provided for this process, and both quantitative and chronological determinations have been carried out on dogs by FREDE and BENNER (197 I) using a photoelectric method. Haemodynamic studies performed by SWEDENBORG; SWEDENBORG et aI. (1971) on dogs have revealed that ADP-induced platelet aggregation is associated with a fall in PVR and, thus, with vasodilation. However, if platelet aggregation is caused by thrombin, there is a simultaneous increase in PVR. This increase is largely abolished, if methysergide (l-methyl-D-lysergic acid butanolamide), a 5-HT antagonist, is given at the same time. Although platelet clumping is observed under both conditions, only thrombin raises PVR and causes intense release reactions. SWEDENBORG and his co-workers have concluded that "it is hard to reconcile that platelet aggregates cause pulmonary obstruction in one case but not in the other". Thus, these investigators believe that vasoconstrictioncaused by 5-HT in their experiments - plays a dominant role, while ADPinduced platelet aggregates produce no mechanical effect at all or are only effective in cases of pre-existing vasoconstriction. However, the results achieved by A. L. HYMAN and associates (1971) in dogs are partly different from these findings. Although these authors also observed an ADP-induced dilation of lung vessels, there was an increase in PVR in the presence of blood platelets. This increase was partly reduced by methysergide. According to HYMAN et aI., the vasodilating action of ADP is disguised by me-

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chanical obstruction of terminal lung vessels and by vasoconstriction resulting from released 5-HT. Nevertheless, in reports published on this subject, the vasodilating effect of ADP on pulmonary vessels has given rise to controversy. SILOVE (19 6 7) describes ADP-induced pressure rise in calf lungs: "ADP has an important pulmonary vasoconstrictor action, although the possibility of an additional thrombotic obstructive action is acknowledged". These findings are in contradiction to the results achieved by REEVES and his co-workers (1967) with calf lungs, who regarded the obstructive effect as cause of the increase in pulmonary pressure. In further experiments performed by KUIDA et al. (1961) on this species, no interference of 5-HT with pulmonary circulation was seen. Thus, released 5-HT is unlikely to playa significant part in the increase in pulmonary pressure. On the other hand, it appears to be generally agreed that 5-HT exerts a pronounced pulmonary vasoconstrictor effect on dogs and cats. However, the haemodynamic action of platelet aggregation simultaneously induced by 5-HT is difficult to assess, since methysergide antagonizes the effect of serotonin at both sites of action. Determining the screen filtration pressure of dog blood, SWANK (1968) demonstrated the remarkable stability of 5-HTinduced platelet aggregates. According to this investigator, "it seems clear that serious pulmonary vascular obstruction can be produced by microemboly (aggregates of platelets and leucocytes) as the result of large infusions of blood". SWANK emphasized the importance of 5-HT for the development of such aggregates, although he also referred to the additional vasoconstrictor action of this compound. It was against this background that the other studies on this subject were performed. Own investigations on cats concerning the effects of DAS, ADP (SCHUMACHER, CLASSEN, 1972) and 5-HT (unpublished findings) yielded the following results: In cats, the i.v. injection of these compounds produced a pronounced, reversible increase in PVR and a simultaneous fall in the platelet count. After the administration of ADP and DAS, there was a highly significant correlation between the amplitude of the pressure rise and the platelet counts of the different animals. DAS produced an extremely violent response. In animals with high platelet counts (up to 700,000/mm.3 in cats), death may occur by right heart failure. The reaction to ADP was much less pronounced and never fatal. 5-HT-induced platelet aggregation and rise in PVR were completely abolished by pre-treatment with methysergide. This compound produced a 20 per cent decrease in the effect of DAS and had no influence on the action of ADP. In cats with experimentally induced thrombocytopenia, DAS failed to interfere with PVR, while 5-HT retained its effectiveness. Thus, the effect of 5-HT on PVR is due to vaso-

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constriction. In some cases, the action of ADP was completely abolished or considerably reduced, in a few animals it remained unchanged. The effect of ADP on PVR of some cats with experimentally induced thrombocytopenia suggests that this compound has another site of action in the pulmonary circulation of the cat. This applies also to adenosine triphosphate (ATP), which may be released from the platelets together with ADP, and which produces a remarkable rise in the PVR of cats, but only a slight platelet aggregation. Experiments conducted by EMMELIN and FELDBERG (1948) provided support for these findings. However, in dogs, ATP was found to lower PVR (SWEDENBORG et aI., 1971). Thus, while ADP and A TP decrease the resistance in the systemic circulation, both compounds show a qualitatively different effect on PVR depending on the species used. It is of interest to note that under the influence of DAS, ADP and 5-HT, comparable obstructions of the terminal vessels by platelet aggregates were discovered in histological studies of pulmonary tissue. Intravital microscopy of the cat mesenterium revealed that intraarterial injections of DAS, ADP and 5-HT resulted in marked embolic obstruction of all sections of the terminal vessels, although the amounts employed failed to produce any vasoactivity. These findings show clearly that even the stability of reversible platelet aggregates is large enough to form haemodynamically active embolic material. In some vessels obstructed by aggregates, erythrocyte congestion is seen proximal to the aggregate, while plasma skimming occurs in the distal part. In accordance with these observations made in mesenteric blood vessels, the administration of DAS leads to a reduction in the haemoglobin content of the blood in the left atrium of up to 20 per cent. This indicates the presence of erythrocyte congestion and plasma skimming in the lungs. These experiments have demonstrated that the obstructive component can play an important part in cat lungs. The controversy about the role of vasoconstriction and vascular obstruction in PVR increase could be settled by intravital microscopy. However, in animal experiments and even more in studies on human subjects, the technical possibilities are rather limited. For this reason, the assessment of the reaction of human lungs poses a difficult problem. HARRIS and his co-workers (1960), STONE and NEMIR (1960) reported on the response of human pulmonary circulation to the administration of 5-HT. These investigators observed that human lungs were remarkably insensitive to the effect of that compound. Thus, 5-HT is unlikely to contribute to the development of the clinical symptoms of human pulmonary embolism. As a consequence, the 5-HT-induced vasoconstriction postulated by SWEDENBORG et al. in dogs, does not necessarily occur in human individuals. The different response of man and dog to ATP also shows that

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the effect of pharmacologically active compounds on pulmonary circulation varies with the species. According to DAVIES and associates (1951), ATP causes an increase in the PVR of human subjects. The effect of platelet aggreg.ates formed outside the body has been shown in persons receiving transfusions. The transfusion of banked blood with high screen filtration pressure fails to produce any reactions of the cardiovascular system of normal subjects, although the aggregates are filtered off by the pulmonary circulation. Human lung is obviously capable of compensating partial obstruction of the terminal vessels to a remarkably large extent. In such transfusions, reactions are known to occur only in subjects with preexisting reduction in the vascular lumen resulting from lesions of various aetiology. Thus, haemodynamic changes in pulmonary circulation are indicative of lacking capability to compensate vascular obstruction. In cases of prolonged sojourn of previously formed microemboli in terminal lung vessels, vasoconstriction is unlikely to occur owing to the involvement of humoral factors. Therefore, the obstructive component predominates in these cases and probably plays a dominat role in the development of microemboli appearing in later stages of pulmonary shock. (MITTERMA YER et aI., 197 0 ). It cannot be assumed that changes in PVR are only due to pulmonary obstruction or to vasoconstriction, especially in human individuals. Both mechanisms seem to coexist. The role of either component depends on the species and the factor inducing platelet aggregation.

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104 . K. A. SCHUMACHER and CH. MITTERMA YER SILOVE, E. D.: Cardiovasc. Res. 5, 3I3 (I97I) STONE, H. H., und NEMIR jr. P.: Ann. Surg. I52, 890 (1960) SWANK, R. L.: J. Trauma 8,872 (1968) SWEDENBORG, J., TAYLOR, G., OLSSON, P.: Scand. J. din. Lab. Invest. 27, 213 (1971) SWEDENBORG, J.: Scand. J. din. Lab. Invest. 27, 321 (1971) DR. K. A. SCHUMACHER, Institut fur Experimentelle Therapie, D-78 Freiburg Hugstetter Stralle 55

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