“And Life-blood streaming fresh; wide was the wound, But suddenly with flesh fill'd up and heal'd”
—John Milton, Paradise Lost1
Thus, in perhaps the greatest single piece of literature in the English language, described John Milton the elective surgery performed on Adam, the resultant hemorrhage, and the method by which hemostasis was secured.
More than 2 centuries later, in 1910, Duke2 provided hemostasis by the transfusion of fresh whole blood. Whole blood continued to be the standard therapy through the 1970s and at very few institutions into the 1980s when the ability to fractionate blood,3 the advent of other technological developments, such as plastic storage bags and preservative and storage conditions specific for components,4 and the transfer of blood collection from individual hospitals to regional centers, resulted in the near pervasive separation of whole blood into red cells, platelets, and plasma in the United States (US), Canada, and Western Europe. Whereas this has been of benefit to those in need of only one component, it likely has been detrimental to those who require all components, as do those suffering substantial hemorrhage. The US Army has used whole blood in conflicts dating from World War I through the present day in Iraq and Afghanistan.5
A spate of retrospective database analyses have attempted, some prospective observations, and now active and planned prospective randomized trials are seeking, to determine whether greater use of plasma and platelets than has generally been transfused since the development of separately stored components, or the use of whole blood, provides superior hemostasis for trauma than does component therapy.6 The US military and civilian practice have already instituted these paradigms as standard transfusion practice for trauma.6
In this issue of Anesthesia & Analgesia, Levy et al.7 highlight what we do and do not know about the critical role of fibrinogen for providing hemostasis for surgery.
We have learned much about coagulation in the ensuing nearly 450 years since Milton's description of surgical hemostasis. The concept of a “coagulation cascade”8 with intrinsic and extrinsic pathways did much to advance our understanding. More recently, the obvious omission (to Duke2 in 1910 and to us, now) of a cellular element, the platelet, has been included in a modified schema.9,10 We have come to understand that the platelet provides the biological and structural base for several zymogens to be converted to active proteases,9,10 and for the essential thrombin burst for converting fibrinogen to fibrin.10–12 For many years it was thought that a critical concentration of each and every coagulation factor was required sequentially to eventually produce fibrin from fibrinogen. Then, Hedner, in a remarkable revelation, discovered that “supraphysiologic” concentrations of activated coagulation factor VII (FVIIa) could “push” the reactions in the absence of coagulation factor VIII.13,14 This “bypass” therapy proved superb for patients with hemophilia A and antibodies to factor VIII, providing them with a hemostatic, including for surgery, where they had none until then, and with little in the way of adverse events.13,14 The concept of a bypass therapy was expanded later to that of a “universal hemostatic.”15,16 Phase II trials in intracerebral hemorrhage (ICH)17 and trauma18 provided proof of concept for this thought. However, both phase III trials for these conditions, although providing proof of hemostasis (as demonstrated by computed tomography–measured decreased hematoma growth in ICH19 and reduced blood use in trauma20), failed to meet their primary regulatory clinical efficacy end points of improved neurologic outcome in ICH and mortality in trauma.
Such single coagulation factor use perhaps led to the thought that fibrinogen might provide hemostasis when administered by itself, especially inasmuch as it is the “final common pathway,” if you will, on the way to the critical creation of fibrin. Although it is fibrinogen, and only fibrinogen, that is converted to the fibrin that is necessary for hemostasis, there are impediments to determining whether treatment with fibrinogen alone can provide hemostatic efficacy (i.e., function as a “universal hemostatic”), while at the same time have few, if any, adverse events.
First, it is of substantial importance that not all fibrin is created equally. Fibrin produced from fibrinogen absent a substantial thrombin burst results in a coarse, rather than fine, structure that is easily degraded by plasmin.21–23 The same thrombin burst is also necessary for the full activation of thrombin-activable fibrinolysis inhibitor (TAFI).24 Additionally, the resistance of fibrin to degradation and deformation is further enhanced by molecular cross-linking induced by coagulation factor XIII.12,25–29 In my view, such failure to produce a proper fibrin and fully activated TAFI may be responsible for what many may regard as “hyperfibrinolysis,” when the etiology may be an inadequate concentration of one or more coagulation factors, or thrombocytopenia or deranged platelet function (the surface on which thrombin is generated), causing the production of a fibrin that is easily lysed with a concomitant failure of full activation of TAFI further enabling such lysis.30
Second, we don't know the minimum in vivo concentration of fibrinogen required to produce adequate amounts of fibrin with a structure that resists fibrinolysis. The single observational report that with blood loss fibrinogen reaches “critical” concentrations earlier than do platelets, prothrombin, or coagulation factors V or VII, assumed the values for critical concentration.31 Other coagulation factors were not evaluated. The differences may not have been statistically significant, and small changes in the assumptions would have produced substantially different results and conclusions. There may be several reasons for the lack of this knowledge. We don't know: (a) the proper method of measurement of fibrinogen for all clinical circumstances. The several methods agree in some, but not all, clinical conditions32; (b) the dose of the various fibrinogen-containing products necessary to reach the unknown adequate in vivo concentration.7 There is an absence of prospective, randomized, dose-finding clinical studies. Whereas the concentration of fibrinogen in specific fibrinogen products is controlled, the concentration in cryoprecipitate is variable; and (c) the appropriate clinical settings and end point(s) for clinical trials to assess the efficacy of these products.
It might seem strange to posit that the appropriate setting for a clinical trial to test a systemic hemostatic agent might be problematic. However, the numbers of elective surgical procedures that are associated with routine, predictable, substantial hemorrhage have decreased, making any potential clinical trial somewhat difficult to contemplate and design. Although major trauma is associated with substantial bleeding, because of the unpredictable nature and intensity of the clinical circumstances, trauma trials are difficult and expensive to perform, and most frequently require a waiver of informed consent (under regulation 21CFR50.24),33 substantially increasing the complexity and expense. Of further substantial importance, the appropriate primary efficacy end point has been sufficiently unclear as to prompt a National Institutes of Health–Food and Drug Administration (FDA) sponsored workshop in December 2010. For many years, I and others have advocated that the efficacy end point of 30-day all-cause mortality frequently recommended by the FDA is not consistent with the pharmacodynamics or pharmacokinetics of agents that act within a very few minutes and for a very limited time to reduce or stop hemorrhage. The panel at the workshop agreed with this thought, indicating that a 6- to 24-hour period is more sensible.34 The panel agreed that an appropriate end point for a hemostatic agent is hemostasis, but acknowledged the difficulty in establishing this objectively. Although clinicians may “know it when they see it,” that is insufficient for an objective end point required by regulatory authorities. Reduction or avoidance of transfusion has been accepted as a surrogate end point for systemically administered proposed hemostatic agents,35,36 and likely continues to be the most achievable of those discussed, although it should be noted that the 3 separate centers of the FDA seem to have differing criteria for efficacy end points for hemostatic agents. An efficacy end point of reduction of transfusion implies the need to study a patient population with sufficient hemorrhage to require a sufficient amount of transfusion to make reduction both feasible and clinically meaningful.
Beyond the issue of efficacy, the current data related to the safety of systemically administered fibrinogen rests largely on its use in patients with congenital deficiencies and self-reported use in the 2 countries (Germany and Austria) where it is approved for surgical hemostasis. There are few comprehensive rigorously assessed data from prospective randomized trials in surgical populations. If one is to draw an analogy from the clinical development experience of recombinant FVIIa (rFVIIa), where adverse event rates differ in differing populations,30 more remains to be learned.
In a larger sense, one may ask whether it is reasonable to expect any one of the elements necessary for coagulation to stand out as a universal hemostatic. Our current understanding of coagulation is that at least 3 separate elements are required: (1) sufficient concentrations of the zymogens to produce the thrombin burst that is necessary to convert fibrinogen to an appropriately structured fibrin and to fully activate TAFI; (2) a sufficient concentration of functional platelets to provide the surface for zymogen activity and binding; and (3) a sufficient concentration of fibrinogen. We do not understand why so many zymogens and proteases are needed, nor do we know fully the concentrations required in a dynamic in vivo, rather than in a static in vitro, setting. An attempt to test 1 of these 3 elements for hemostasis related to surgery or trauma, while controlling the other 2, is likely to be exceedingly difficult. Clinical trials incorporating interventions for all 3 (e.g., administration of several doses of platelets, multiple doses of several coagulation factors or supraphysiologic concentrations of rFVIIa, and fibrinogen, each) would not seem possible at this juncture. Despite these considerations, it should be noted that rFVIIa did provide evidence of hemostasis in 2 phase II and 2 phase III trials of widely differing causes of hemorrhage.19,20
Nevertheless, clinical trials with fibrinogen offer the exciting possibility of testing our understanding of static coagulation as it applies to the dynamics of surgery and further quantifying the necessary constituents for the unspoken intervening steps between a “wide wound”/“streaming life-blood” and it being “with flesh fill'd up and heal'd.”1
Name: Richard B. Weiskopf, MD.
Contribution: This author wrote the manuscript.
Conflict of Interest: The author has a relationship with or consults for the following companies and organizations that have an interest in erythrocyte and/or plasma transfusion: US Food and Drug Administration, US National Heart, Lung, and Blood Institute/National Institutes of Health, US Army/ Department of Defense, CaridianBCT, CSL Behring, Entegrion, OPK Biotech, and Sangart Inc. The author was project/corp VP and Executive Scientific Advisor at Novo Nordisk A/S, 2005 to 2007.
This manuscript was handled by: Steven L. Shafer, MD.
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