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Semin Thromb Hemost 2011; 37(4): 337-338
DOI: 10.1055/s-0031-1276581
PREFACE

© Thieme Medical Publishers

Forgotten Factors in Hemostasis and Thrombosis

Marcel Levi1 , Joost C.M. Meijers1
  • 1Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Publication History

Publication Date:
30 July 2011 (online)

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Science is a systematic, comprehensive, and often slowly progressing activity. However, scientific topics can quickly become fashionable and attract a lot of attention. Due to a new finding, emerging new diagnostic or therapeutic options, or just by serendipity, a scientific subject can suddenly be center stage, and articles from all parts of the world immediately start to appear in the international biomedical literature. This phenomenon is invariably occurring in the field of hemostasis and thrombosis. A good example is the genetic variant of coagulation factor V causing resistance to activated protein C (factor V Leiden), which has generated 3500 full-length articles in 15 years or the almost 1000 papers on the von Willebrand factor cleaving protease ADAMTS13 in the past 10 years.[1] [2] The development of recombinant human activated protein C for the treatment of sepsis and disseminated intravascular coagulation has stimulated a lot of attention to research on the interaction between inflammation and coagulation,[3] with a more than threefold increase in the number of papers on this subject in the past 10 years compared with the previous 10 years. Likewise, subjects that are hot topics for a while may become less popular in a next period and can even be almost forgotten by the research community. There are many examples, also in the field of hemostasis and thrombosis, as illustrated in Fig. [1] for the once fashionable factors heparin cofactor II and plasminogen activator inhibitor (PAI)-2. However, it may be worthwhile not to forget altogether these orphan factors because they may again take their place in the spotlight all of a sudden or because the insight on the function and properties of these proteins may be helpful unexpectedly to explain a new pathway or mechanism.

Figure 1 Number of publications on heparin cofactor II (circles) and plasminogen activator inhibitor-(PAI)-2 (squares) in recent years.

This issue of Seminars in Thrombosis and Hemostasis is devoted to some of these (almost) forgotten factors in the field. Heparin cofactor II is an anticoagulant protein, targeting thrombin but has many other properties, as outlined in the article by Rau et al.[4] Another protein involved in the inhibition of coagulation is protein C inhibitor, originally identified as an inhibitor of activated protein C but also capable of inhibiting various other proteases and apparently involved not only in coagulation and fibrinolysis but also in cancer spread, wound healing, and fertility.[5] The link between coagulation and other plasma protein systems, notably the complement system, is illustrated by two articles, one focusing on C4b-binding protein (that is also the main carrier protein of free protein S) and C1-esterase inhibitor (that is an important modulator of serine protease activity in coagulation and fibrinolysis).[6] [7] A typical example of a part of the coagulation system that once attracted a lot of attention but has become less prominent is the contact activation system. The contact system was originally thought to be one of the most important initiating pathways of coagulation, but due to recent insights that coagulation almost always proceeds by the tissue factor-factor VII route, it has been assigned a less important role in hemostasis in vivo. Nevertheless, new research points to a role of the contact system in fibrinolysis, thrombosis, and hemodynamic regulation, as reviewed by Maas et al.[8] In their article they also discuss new insights on the initiation of contact system activation, whereby misfolded proteins, collagens, and polyphosphates have been identified as the long-sought activators of the contact system in vivo. Because most of our diagnostic tests in coagulation focus on fibrin formation, the importance of proper fibrin cross-linking may sometimes be overlooked. In this process, factor XIII plays a crucial role. Factor XIII can really not be classified as a “forgotten factor”; however, acquired factor XIII deficiency is a rare condition that has not received a lot of attention recently. This condition is reviewed by Ichinose.[9] In between coagulation to fibrinolysis, histidine-rich glycoprotein interacts with heparin and heparan sulfate, fibrinogen, and plasminogen. The function of this molecule seems to extend beyond these two systems to a role in innate immunity as well.[10] In the fibrinolytic system, two factors that attracted a lot of attention in the past have been somewhat obscure in the literature of the last 10 years, that is, vitronectin and PAI-2, respectively.[11] [12]

Interestingly, all the articles in this issue of Seminars in Thrombosis and Hemostasis show that although the forgotten factors may have lost some of their popularity, new insights on their properties and function are still being generated, although at a slow pace. It is likely that these new insights at a certain point may fill a gap in a previously puzzling part of biology or a disease mechanism that may lead to renewed increased attention. Hence factors can be forgotten but are not gone forever.

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