Although there is some legitimate controversy on the matter,⁸ it would seem that Andrew Buchanan deserves the credit for the discovery of a “substance” intrinsic in blood that could form an insoluble substance when added to blood or other “fibrogeneous” fluid such as hydrocele or ascites.^9,10 It was noted that hydrocele or ascites did not clot without the addition of their fibrin ferment. Buchanan isolated a “washed blood-clot” from blood which had been added to 6–10 volumes of water, stirred for 5 minutes, and allowed to stand for 24 hours. The washed blood-clot was isolated by filtration through a coarse linen cloth. The isolated washed blood-clot retained coagulant activity when added to blood or hydrocele. While blood would clot in the absence of exogenous material, hydrocele and other “fibriniferous” fluids would clot on the addition of the washed blood-clot. The isolated washed blood-clot could be dried and stored. It was noted that the addition of “spirit of wine” (distilled wine, mostly likely what would be considered brandy today) preserved activity. Gamgee¹¹ repeated and extended Buchanan’s experiments, presenting evidence that the washed blood-clot was fibrin (Faserstoff) and did retain coagulant activity, which he described as fibrin ferment. Subsequent studies with somewhat better characterized reagents confirmed that thrombin did bind to fibrin^12,13 and that such binding was associated with the conversion of fibrinogen to fibrin. Later studies showed that thrombin generated in plasma could be adsorbed to fibrin during the process of fibrinogen clotting.¹⁴ More sophisticated studies performed 60 years later showed that the majority of thrombin generated in situ under dynamic conditions is incorporated into the fibrin thrombus.¹⁵ The inclusion of the tripeptide, GlyProArgPro which inhibits fibrin polymerization, increased the amount of thrombin-antithrombin detected. Early work had designated fibrin as antithrombin I.^16–18 Thrombin bound to fibrin does retain enzymatic activity.^19–23 This work with purified proteins supports the earlier the observations by Buchanan and Gamgee^9–11 that crude fibrin isolated could contain bound thrombin, which would still be active. Wilner and coworkers¹⁹ showed that streptokinase digested the complex of thrombin with fibrin, with the release of active thrombin, which was likely still bound to soluble fibrin degradation products.²⁰ Thrombin bound to blood platelets also retained activity.^24,25 Platelets were also shown to have antithrombin activity by Tullis and coworkers.^26,27 Gamgee¹¹ was able to elute the fibrin ferment from the isolated washed blood-clot in what might have been the first purification of thrombin; in later work, Schmidt was able to form thrombin from prothrombin isolated from plasma.^28–31 And Howell,³² also in later work, isolated “thrombin” from porcine fibrin (obtained by the whipping of porcine blood). “Thrombin” was eluted with NaCl (8 gm/L; 0.14 M) and the turbid solution subjected to repeated extraction with chloroform until a clear solution was obtained. However, the properties of the product raise some question, as it was said to be stable to boiling. There are reasons to suspect the quality of the early fibrin ferment preparations and the relationship of such presentations to thrombin. However, this author acknowledges that it is very difficult to totally inactivate thrombin. The product obtained by Howell could be dialyzed (collodion tubes [nitrocellulose membranes]^33–35) in water but was said to be unstable in the absence of salt. The material could be precipitated with alcohol or ammonium sulfate (half-saturation). The material also provided a positive biuret reaction and a positive Millon reaction (tyrosine); it was also positive for tryptophan. Howell’s product did behave as a globulin (insoluble in water, soluble in dilute salt solution). Gamgee¹¹ had previously shown that his fibrin ferment also behaved as globulin (insoluble in water) and was inactivated by heat, suggesting that the isolated material was a protide³⁶ (protein). There was some suggestion by Gangee¹¹ that the isolated material was an enzyme; hence, the term ferment³⁷ was used to describe the activity. In later work it will be seen that the suffix -ase is attached in a combination word, such as in thrombokinase, to indicate designation of the material as an enzyme. As noted by Gamgee,¹¹ Buchanan’s work had been largely ignored, possibly obscured by the work of Alexander Schmidt who, for good reason, is frequently given the credit for the discovery of thrombin (fibrin ferment) for work first appearing in 1861,^28–30 culminating with a “magnum opus” in 1892.³¹ It is accepted that Schmidt was the first to use the term thrombin to describe fibrin ferment activity based on his observation on the formation of a intravascular thrombus following administration of thrombin. In his early work, Schmidt questioned as to whether fibrin ferment was an enzyme favoring a concept where fibrin ferment combined with fibrinogen in the presence of a paraglobulin to form fibrin. In later work,³³ Schmidt did promote the enzymatic nature of fibrin ferment, and together with others including Hammarsten,³⁸ developed the concept of soluble fibrin as an intermediate in the formation of a fibrin clot. As will be discussed later, there were several theories for the formation of fibrin. There was a lively discussion of the nature, formation, and mechanism of action of fibrin ferment during this period of time (1860–1930).^5,6,39,40 As will be shown later, discussion over the identity of thrombin as an enzyme continued into middle of the 20th century.^41–50 Chargaff,⁴¹ about whom I will write more later, noted: “Many of these discussions degenerated into mere exercises in terminological dialetics.” I observe that blood coagulation has been cursed by terminology issues, leading to the formation of an international committee on nomenclature, which met in exotic places to assign Roman numerals to the various factors. I do grant that factor XI is a more useful term than “plasma thromboplastin antecedent,” so there is some merit in the Roman numeral system. On the other hand, there was some grousing by an eminent hemophilia specialist that a patient with Christmas disease would not remember that he is deficient in factor IX or factor VIII, just that he had hemophilia. I would further observe that nomenclature is a problem that continues in science and may be getting worse, eliciting continuing comparison to the biblical tale of the Tower of Babel.^51–53 For someone like myself who has diverse interests, a Babel fish⁵⁴ may be needed.

In 1905, Paul Morawitz² attempted to rationalize the information of the past several centuries into a model for the coagulation of blood. He postulated that four factors were important for the formation of a blood clot: prothrombin (preferment; thrombogen), calcium salts, fibrinogen, and thrombokinase. The Morawitz hypothesis has been referred to as the four-factor model.⁵⁵ Thrombokinase was a factor considered to be an enzyme; hence, the term kinase. derived from the disintegration of platelets and leu...