Antithrombotic Drugs in Thrombosis Models

Josef Hladovec

• Publisher: CRC Press
• Year: 2020
• Print ISBN:
  9780367450984
• eBook ISBN:
  9781000141689
• Topic: Medicine
• Subtopic: Hematology

Antithrombotic Drugs in Thrombosis Models presents a critical review of the use of thrombosis models and an original, highly sensitive methodology for testing antithrombotics based on a more adequate understanding of thrombotic processes. The methods form an integrated system stressing particularly the plurifactorial and global character of thrombosis and the key role of a generalized mild endothelial lesion. Packed with illustrations, this book documents the effectiveness of the system through the screening of a series of acknowledged and potential antithrombotics, and includes a unique study of their mutual combinations. Special emphasis is placed on the importance of biomodels for preliminary testing of antithrombotics. This book is particularly useful to researchers in pharmacology and the pharmaceutical industry; however, those interested in drug research and the field of cardiovascular medicine will benefit as well.

Chapter 1

INTRODUCTION

Ever since the recognition of the pathogenetic role of thrombosis, that is since the mid- 19th century, many authors have attempted to find effective ways to dispose of this killer number one. First, it was necessary to know more about the mechanism of thrombus development.

One line of research followed the humoral changes which would predispose to or even cause thrombosis. This line leaned heavily on biochemical methods and scored tremendous successes particularly in our times. Another line represented a predominantly experimental approach which, in distinction to the first one, attempted to see thrombosis as a whole in model situations induced in experimental animals. This line has been present since the start of thrombosis research and has been never completely abandoned. Nevertheless, it was very often, and not to the benefit of our knowledge, eclipsed by the successes of the biochemical line of research. The third line is a clinical and pathological one. It supplies us with new and alarming data about the deadly character of thrombosis, leads to attempts to recognize this process in time and to offer more or less effective prevention and even treatment.

It is necessary to state straightly that the problem of effective prevention and treatment remains, in general, unsolved. Nevertheless, an impression is present all the time that more effective ways are feasible and waiting behind the door for discovery. One way to discover them is to pursue the first successful biochemical line; accumulation of further and more detailed information about new systems and factors which would once more appear as the most important and ultimately decisive ones. A probably more useful way would be to proceed along the second experimental line which alone can mediate healthy relations with the clinic and serve also as a corrective of the excesses of sometimes exaggerated self- assurance of the first research line.

Chapter 2

THE RATIONAL BASIS OF THROMBOSIS MODELS

I. THE THROMBOSIS TRIAD

In this chapter thrombosis will be dealt with as a general problem even though differences undoubtedly exist between thrombosis on the arterial and venous side, and even more so, between both and the disseminated intravascular coagulation. This general view allows us to pay particular attention to the traits and mechanisms common to thrombosis in all localizations and then point out differences if necessary.

Essentially, thrombosis is a multifactorial process, just as almost all serious and still incompletely understood and controlled circulatory derangements of our days are. The simple ones have already been solved. It is generally handed down that the multifactorial character of thrombosis was discovered by Virchow¹ who formulated his triad as a combination of stasis, inflammatory changes in the vessel wall, and changes in the properties of blood. It would be only fitting to mention that all three factors were recognized some time before Virchow by the Viennese pathologist of Czech origin, Rokitansky, in his “Krasenlehre”.² He pointed out in a quite up-to-date way the role of systemic humoral changes, whereas Virchow emphasized in his somewhat polemic studies mostly local conditions of thrombus development. On the other hand, credit is due to Virchow for using an experimental approach and for having been the first to formulate the concept of embolism. Virchow mentioned that he introduced the term thrombosis, even though the term thrombus is of a much older date and was used, e.g., by Galenus. Rokitansky distinguished thrombi developing on the basis of vessel-wall inflammation combined with stasis and assigned an important role to the liberation of materials from the vascular wall in the process (“Exudate”). This reminds us of the modern knowledge about the secretory function of the endothelium. He also distinguished inflammation which was secondary to the development of thrombus, but in his eyes thrombus may be the result of inflammatory processes in other areas of circulation outside the site of thrombosis or may be a consequence of “einer aus einem inneren Momente (Blutkrankheit) hervorgegangener Blutgerinnung”. He knew well the differences between arterial and venous thrombi and recognized thrombolysis as a “feine Zertheilung” or “Auflosung” of thrombi. A close relation existed in his concept between a vascular inflammatory reaction, blood clotting, and thrombus development on one side and atherosclerotic processes on the other. He also described “die Prozesse von Stase und Blutgerinnung in den verschiedensten Abschnitten des Capillargefasssystems” that came to be known much later as disseminated intravascular coagulation. All that may be summarized in the statement that Rokitanski’s views of thrombogenesis were characterized by unusual dynamism and anticipation. As his ideas were published in advance of Virchow’s it would probably be just to call Rokitanski the father not only of modern atherosclerosis theories, but also of current concepts of thrombosis. This is not meant to diminish the credit due to Virchow in the field of our knowledge about thrombosis. He has, for example, introduced the term fibrinogen and stimulated the studies of A. Schmidt who laid the ground to our present knowledge about the coagulation system.

If the thrombogenesis triad is approximated to the present state of the problem, the three factors have now rather the form of three groups of related factors (Table 1). All these factors contribute to the production of a special state of the organism, mostly existing for a limited period of time and confined particularly to a circumscribed site of the vascular system to result in thrombus formation. Meanwhile, thrombosis may be defined as local adhesion to the vascular wall of more or less structured masses accumulating locally from constituents of flowing blood as a consequence of a deviation of hemostatic mechanism and leading to a partial or complete obstruction of blood flow.

TABLE 1
Thrombosis Triad and its Contemporary Correlates

Originally	Presently
Humoral factor	Blood clotting
(“crasis”)	Fibrinolysis
	Platelets
Stasis	Hemodynamic factors
	Hemorheologic factors
Vascular lesion	Vascular lesion

II. THROMBOSIS FACTORS

A. Humoral Factors

1. Blood Clotting System

Sometimes a primary role in the development of thrombosis is ascribed to changes in the blood clotting system. The meaning of the designation “primary”, however, is not very clear. If it is accepted that thrombosis is a multifactorial process, the primary contribution is meant to be made by such factors which would produce thrombosis alone, without the preliminary assistance of other factors implicated in the process only as secondary consequences. However, this is not the case even in hereditary blood clotting defects connected with a predisposition to thrombosis because they exist mostly for a lifetime whereas thrombosis develops only in case of favorable coincidence with other contributing factors. Nevertheless, it is possible to admit their important influence.

If the clinical experience is taken into account in only a portion of thrombosis patients, between 10 and 20%, a hereditary defect of a known blood clotting factor or inhibitor may be of such an important influence, or may have substantially contributed to the development of thrombosis.^{3, 4, 5, 6} Antithrombin III deficiency, caused either by the lack of or a qualitative defect in the molecule, was found in about 2% of thrombosis cases. Deficiency of protein S was estimated in 10% of cases up to 40 years of age. The frequency of factor C defects is still difficult to assess. Other hereditary defects such as dysfibrinogenemias, factor XII deficiency, and sickle cell anemia are infrequently connected with the occurrence of thrombosis. Another portion of thrombosis patients may have inherited defects of the fibrinolytic system such as deficient or defective plasminogen, deficient tissue plasminogen activator (tPA) synthesis or release, as well as increased plasminogen activator inhibitor (PAI). This particularly concerns patients with recurrent attacks of deep vein thrombosis. Of course, not all possibly important factors and their hereditary defects have been properly identified as yet. Some factors inhibiting endothelial synthesis, accumulation or release of blood clotting or fibrinolytic factors or endothelial viability may exist as well, such as in homocysteinemia.^{7, 8} A special kind of a hereditary predisposition in thrombosis patients is suggested by the high freqency of some HLA antigens (Cw 4)⁹ and the prevalence of blood group A.^{10, 11, 12, 13, 14}

As mentioned above, in patients with hereditary predispositions relatively weak additional provocation is needed for thrombosis development and it is in this subgroup of thrombosis patients that humoral factors may play an important role. However, even under such conditions the process of thrombosis is still multifactorial.

A rather different situation exists in the case of acquired humoral defects. They may be manifested as hypercoagulable states, if defined on the basis of laboratory tests, or...

Table of contents

• Cover
• Title Page
• Copyright Page
• Preface
• The Author
• Table of Contents
• Chapter 1 Introduction
• Chapter 2 The Rational Basis of Thrombosis Models
• Chapter 3 Basic Methods
• Chapter 4 Effects of Antithrombotics and Results of Drug Screening
• Chapter 5 Drug Combinations
• Chapter 6 General Conclusions
• Index