Problems about Thrombogenic Hypothesis of Atherogenesis

Hypothesis, firstly proposed by Rokitansky in 1852 and revived by Duguid in 1946, that atherosclerotic plaques result, at least partly, from organization of fibrin thrombi, is fascinating from view point of blood coagulation, although direct evidences have been lacking. Authors have demonstrated that levels of β-thromboglobulin and platelet factor 4 decreased following administration of antiplatelet agents and that concentration of antithrombin III in plasma lowered following decrease in levels of vitamin K dependent procoagulants by administration of warfarin. These results support Astrup's hypothesis that minimal fibrin deposition and its lysis continuously occurrs on vascular intima in normal subjects. Assuming that these hypotheses are true, hypercoagulability of blood in a broad sence may accelerate deposition of fibrin on vascular wall and may lead to progression of atherosclerosis.Purpose of this study is to elucidate this problem from investigation of blood constituents which affect removal of activated clotting factors which are most important in formation of fibrin. Two major parameters which affect blood viscosity, namely hematocrit values and fibrinogen content, and two most important inhibitors of activated procoagulants, namely antithrombin III and α2-macroglobulin, were compared to grade of atherosclerosis of coronary and cerebral arteries classified grossly with naked eyes in serial 537 autopsied cases without cancer or DIC.Following results were obtained: Hematocrit values were significantly higher in patients with marked atherosclerosis of cerebral artery. There were no statistically significant correlations between levels of inhibitors or fibrinogen and the grade of atherosclerosis, although total antithrombin levels, which were generally lower in males because of higher content of α2-macroglobulin in females, decreased in females with severe atherosclerosis. However, a 54-years old male with congenital dysfibrinogenemia, in whom delayed convertion rate of fibrinogen into fibrin and impaired platelet aggregability induced thrombin and angiographically marked sclerosis of cerebral artery were demonstrated, had repeated attack of cerebral infarction, although risk factor of arteriosclerosis was lacking but hypertension.From these results, it is concluded that evidences in favor of the thrombogenic theory of atherosclerosis is insufficient and that mild suppression of blood clotting system is not enough to protect one from arteriosclerosis.