Immunohistochemical Demonstration of the Reticuloendothelial Clearance of Circulating Fibrin Aggregates

Abstract

PLATES 83 AND 84(Received for publication, July 6, 1962) When thrombin is administered intravenously to rabbits for several hours at a rate just insufficient to produce intravascular thrombosis, there is nevertheless conversion of much of the animal's circulating fibrinogen to fibrin (1). In most instances, no detrimental effect is observed, and no extensive fibrin deposition is found (2). This absence of pathologic alterations in the face of extensive intravascular fibrin formation has generally been ascribed to the efficient lysis of fibrin by plasmin and other blood proteolytic enzymes. While local activation of plasminogen may be responsible in the rabbit for eliminating fibrin already deposited, recent evidence (2) has indicated that the bulk of fibrin aggregates formed in the circulating blood are rapidly removed by the reticuloendothelial system in a manner similar to the efficient clearance of foreign particulate matter and colloidal materials. It was shown that blockade of the reticuloendothelial system in rabbits receiving intravenous thrombin infusions regularly resulted in massive fibrin deposition in the terminal vascular bed. The major lesion, bilateral renal cortical necrosis, was indistinguishable from that of the generalized Shwartzman reaction which has classically been elicited by bacterial endotoxins.In the present report immunohistochemical studies have provided direct evidence for the phagocytic clearance of fibrin by demonstrating the accumulation of this material selectively within the reticuloendothelial cells of the liver and spleen after the administration of thrombin or endotoxin. These observations further substantiate the hypothesis (2) that the generalized Shwartzman reaction in the rabbit results from the failure of the reticuloendothelial system to adequately clear the circulation of fibrin aggregates formed during systemic blood coagulation initiated by endotoxin.

Platelets and the Shwartzman Phenomenon

“…Many of the agents used to provoke the generalized Shwartzman phenomenon accelerate coagulation (4)(5)(6)18). In in vitro studies (16)(17)(18), platelets are required for the demonstration of acceleration of eoagtflation.…”

“…Baltimore) PLATES 17 AND 18 (Received for publication, September 10, 1954) There are many indications that the effects of endotoxin upon blood vessels (1), leucocytes (2,3), and coagulation (4)(5) are important in production of the Shwartzman reaction. The effects of endotoxin upon blood vessels and leucocytes cannot be disputed, but involvement of platelets in the intravascular clotting of the Shwartzman phenomenon has never been established with certainty.…”

Quantitative Aspects of Blood Coagulation in the Generalized Shwartzman Reaction: 1. Effects of Variation of Preparative and Provocative Doses of E. Coli Endotoxin

“…Previous investigations have shown that each injection of endotoxin activates the clotting mechanism. However, the first apparently produces only transient injury to the reticuloendothelial system (RES) so that clearance of circulating endotoxin [7], clotting intermediates [8], and fibrin [9,10 ] is efficiently performed. The second injection of endotoxin, on the other hand, leads to massive intravascular formation of fibrin which cannot be removed due to a now severely impaired RES [I I] and, in the rabbit, an ineffective fibrinolytic system [12, 131. It has been shown by others that the concentration of endotoxin used for each injection and the interval between doses are critical in producing the GSR [14,15,161.…”

Isotopic studies of therapeutic anticoagulation with a coagulating enzyme

“…When coagulation takes place at a slow rate, the small polymers that are formed do not obstruct the microcirculation and are rapidly cleared by the reticuloendothelial system (18,19). As a result of the intravascular coagulation, the disappearance of labeled fibrinogen from the plasma is accelerated (20): the radioactivity of clottable and nonclottable protein decreases in the plasma in a continuous manner.…”