Historical Perspective
In 1842, T.W. Jones, a British physician, asked the question: Why doesn't the blood circulating in the vessels coagulate?¹⁴⁷ This question has intrigued blood coagulation researchers ever since. In 1845, Rudolph Virchow, the German physician and father of pathology, responded to the question raised by Jones by stating that under certain circumstances circulating blood does coagulate, and he speculated what those pathologic states might be.¹⁴⁸ Almost simultaneously, A. Trousseau, a French physician, observed that circulating blood does coagulate in the vessels in certain conditions and reported clinical observations to support Virchow's speculation.¹⁴⁹ Trousseau's syndrome is the name still used when thrombophlebosis is associated with malignant diseases.
   
In 1893, Dastre first proposed the term "fibrinolyse" for his observations on the dissolution of blood clots.¹⁵⁰ However, his were not among the earliest observations on fibrinolysis. John Hunter, the eighteenth-century London surgeon, included his observation on clot dissolution in his famous treatise on blood.¹⁵¹ In 1887, Green's publication of his studies of the effect of sodium chloride on the dissolution of plasma clots also preceded those of Dastre.¹⁵² In 1903, Delezenne and Pozerski reported activation of serum proteolytic activity by chloroform,¹⁵³ and four years later, Opie and Barker separated albumin from globulin and proteolytic activity was associated with the globulin fraction.¹⁵⁴ In 1933, rapid lysis of plasma clots by extracts of beta-hemolytic streptococci was noted by Tillet and Garner,¹⁵⁵ and in 1944 Kaplan demonstrated that the streptococcal factor was an activator for the proteolytic enzyme precursor in human plasma.¹⁵⁶

Coagulative and Fibrinolytic Pathways
The twin coagulative and fibrinolytic systems are similar in many ways and have been extensively investigated and reviewed.^157-160 Both systems are activated, amplified and counterbalanced in biologic phenomena involving injury, inflammation, repair responses, metastatic cancer of spread and degenerative disorders. Both systems are composed of inactive precursors that are converted into active enzymes of serine protease type.¹⁶¹ Both systems involve intrinsic (plasma) and extrinsic (tissue) activation mechanisms which trigger a common pathway. In the coagulative system, the final common pathway involves polymerization of fibrinogen into fibrin, while that in the fibrinolytic system it involves activation of plasminogen. And, as we show later in this article, the primary mechanisms underlying both systems are related to oxidant phenomena in the circulating blood (which we designate as oxidative coagulopathy) as well as those which affect cell and plasma membranes and cytosol (which we collectively designate as AA oxidopathy). Even though the coagulative and fibrinolytic systems are generally regarded as two discrete enzymatic pathways, in reality the intrinsic pathways of the fibrinolytic system is coupled to the intrinsic pathways of the coagulative, so that clot formation and resolution are initiated concurrently and perpetuated in tandem. We introduce the term clotting-unclotting equilibrium (CUE) in this article to integrate the oxidative nature of events that lead to the concurrent phenomena of clot formation and clot resolution.
   
Abnormal coagulative phenomena within the circulating blood occur in diverse clinicopathologic entities such as eclampsia, anaphylaxis, localized and generalized Shwartzman reactions, hemorrhagic diathesis in clinical and experimental acute viral infections, bacterial endotoxic shock and others.¹⁵⁷ Some turn-of-the-century investigators mistook such coagulative phenomena within the vascular lumina—fibrin threads and amorphous deposits, as well as the classical thrombi—as postmortem events. However, this mistake was recognized by Ingerslev and Teilum, who in 1946 described fibrin thrombi in hepatic periportal sinusoids in the liver of women who survived eclampsia.¹⁶² Even though the concepts of pre-thrombotic and hypercoagulable states have drawn considerable interest^{158-161,163,164}; however, the definitions of such states varies from author to author and discussions of the subjects have been confined to clinical thrombotic-hemorrhagic events. To our knowledge the central role of chronic, insidious clotting-unclotting disequilibrium in the pathogenesis of IHD has not been recognized.
   
The occurrence and patterns of free radical injury to the myocardium, the conducting system of the heart, and coronary arteries have been investigated extensively with ischemia-perfusion studies.^165-170 Specifically, free radicals, particularly superoxide anion (O2._) and hydroxyl radical (OH*), are produced during and after ischemia and reperfusion, and cause oxidative functional and structural injury to the heart, including the loss of myocardial contractile function. Superoxide anion is a relatively weak oxidant and owes most of its destructive potential to its ability to generate hydrogen peroxide by reacting with molecular oxygen. Hydrogen peroxide, in turn, generates highly toxic OH* radicals in the presence of transition metals such as iron and copper.
   
Fibrinolysis is generally assumed to occur only as a part of the spectrum of pathologic coagulative disorders. Our morphologic observations challenge this assumption. We sometimes observe congealed plasma and microclots in healthy subjects without history or demonstrable evidence of any coagulative disorders. We have also observed, as illustrated in this article, that such congealing of plasma and microclot formation is easily reversed by addition of antioxidants, proving that such coagulopathy is oxidative in nature. Our microscopic findings show that clotting and unclotting within circulating blood occurs with high frequency in a variety of cardiovascular disorders as well as in otherwise healthy subjects with established risk factors of IHD. In states of accelerated oxidative molecular injury, the rate of oxidative coagulation exceeds that of fibrinolysis, and the various patterns of oxidative coagulopathy and AA oxidopathy are readily observed. Clinicopathologic entities that are associated with disseminated intravascular coagulation, in our view, represent more advanced stages of the same process. While disseminated intravascular clotting in many acute and chronic disorders has been thoroughly studied, the occurrence and extent of such phenomena in the insidious development of molecular and cellular lesions that lead to IHD, to our knowledge, has not been previously recognized.

SPONTANEITY OF OXIDATION IN NATURE AND DISEASE
We include below brief comments about some fundamental aspects of the phenomenon of oxidation as a framework for our discussion of oxidative coagulopathy. Oxidation is a spontaneous process—it requires neither an expenditure of energy nor any outside cues. A flower wilts spontaneously; a wilted flower does not "unwilt" spontaneously. Fish rot spontaneously; rotten fish do not "unrot" spontaneously. Cut grass decomposes spontaneously; decomposed grass does not "undecompose" spontaneously. Thus, spontaneity of oxidation in nature is the natural phenomenon that provides the core mechanism of molecular injury in biology. Stated in another way, spontaneity of oxidation is nature's grand scheme to assure that no oxygen-utilizing form of life remains immune to the immutable law of oxidative death. Oxidation plays a similar role in the decay of inanimate matter as well. Iron rusts spontaneously; rusted iron does not "unrust" spontaneously. Reduction, the other side of the redox equation of life, requires expenditure of energy.

What is the energetic basis of spontaneity of oxidation in nature? A simple analogy may be used to answer this question. A boy is playing with a ball attached to a string. He keeps the ball flying in an orbit around him by moving his extended arm in a circle above his head. In this circumstance, the kinetic energy of the ball seeks to move the ball away from the boy, but it is counterbalanced by the pull of the string on it so that the ball stays in a circular orbit. If the boy lets go of the string, the ball will spontaneously fly away. The same thing would happen if the boy were to spin the ball with a greater force than can be sustained by the string. The above analogy may be completed by imagining that the ball moves in elliptical orbits—the string has extreme elasticity and pulls the ball closer to the boy's head by shrinking at one time and allows the ball to move far away from the boy by stretching at another time. (Physicists believe that atoms exist in a simultaneous particle-wave state determined by a particle-wave probability distribution.) A similar set of conditions governs the motion of electrons as they spin around the nucleus of an atom. Thus, spontaneity of oxidation (electron loss) is in reality a function of the kinetic energy of electrons that favors their outward movement, hence their loss. Thus no external source of energy is required in oxidation.
   
Electrons within atoms and molecules do not orbit the nucleus of an atom in the sense that the earth orbits the sun. Rather, electrons occupy regions of space called orbitals, which can hold no more than two electrons. A characteristic of electrons in a given orbital is that they demonstrate opposite spins. Within a molecule, two electrons sharing the same orbital exist in a bond called a covalent bond. A lone electron within an orbital is considered unpaired. This leads us to the definition of a free radical: any atomic or molecular species capable of an independent ("free") existence that contains one or more unpaired electrons in one or more orbitals. We may point out that carbon- and sulfur-centered radicals generally react with oxygen with greater affinity than others included in the table given below.
   
A partial list of common naturally occurring free radicals is shown in the following table adopted from Halliwell.¹⁷¹

O2 + 4H+ + 4e- = 2H2O

Under ordinary circumstances, reduction of oxygen by cytochrome oxidases in the above reaction does not release reactive oxygen radicals. This is assured by transitional metal ions such as iron, copper, vanadium and titanium, which are carried in the active sites of cytochrome oxidases. Such metal ions occur in variable states of oxidation, and changes in such states facilitate transfer of single electrons in an orderly fashion in which various partially reduced forms of oxygen are held bound to the metal ions. These ions also play essential roles in spontaneous oxidation (autoxidation) of several nonradical compounds including ascorbic acid; thiols such as cysteine, homocysteine and reduced glutathione; catecholamines such as epinephrine and norepinephrine; and a host of amines such as 3,4-dihydroxyphenylalanine (DOPA) and 6-hydroxydopamine.
   
Molecular oxygen has an interesting "love-hate" relationship with electrons. It avidly picks up free electrons in its vicinity, then just as avidly spins them out. In a vacuum, electrons travel at the speed of light. Even though the speed of an electron in tissues would be expected to be drastically reduced, the electron-oxygen transactions must still take place at amazingly fast speeds. During oxidative phosphorylation in the generation of ATP, molecular oxygen accepts an electron—is reduced—to become superoxide. Superoxide then loses its electrons spontaneously—is oxidized—in initiating the free radical chain reactions that result in the formation of peroxides, oxyacids, aldehydes and hydroxyl radicals. Such free radicals oxidize proteins of coagulation cascades, thus triggering oxidative coagulopathy, which further fans the fires of AA oxidopathy. However, our high-resolution microscopic observations described in this article lead us to conclude that accelerated oxidative stress on components of circulating blood is neither confined to oxidative injury of coagulation pathways nor, indeed, are the coagulative phenomena the initial events. We introduce the term AA oxidopathy to encompass a broad range of oxidative events that include: 1) peroxidation of plasma and cell membrane lipids; 2) oxidative permutations of plasma and cell membrane sugars and proteins; 3) accelerated autoxidation of nonenzymatic plasma antioxidants such as thiols and ascorbic acid; 4) inactivation or saturation of plasma enzymatic antioxidant mechanisms; 5) endothelial injury; and 6) later oxidative injury to subendothelial collagen and the muscularis of the arterial wall. Oxidative modification of LDL cholesterol—widely believed to be the critical event in atherogenesis—is, in our view, a relatively less significant event. We return to this essential issue later in this paper.