BIOENGINEERING
Make the bleeding stop Karim Brohi A synthetic polymer that cross-links fbrin shows promise in the management of hemorrhage (Chan et al., this issue).
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Tirty people will bleed to death from their injuries while you read this article. Trauma hemorrhage is one of the world’s biggest killers, responsible for more than 2 million deaths every year. Deaths occur quickly, from exsanguination or failure to control bleeding, and late from the complications of profound shock, including multiple organ failure and sepsis. Casualties with massive hemorrhage approach a 50% mortality rate, even if the patients reach a hospital. Yet, the majority of these deaths are potentially preventable. If bleeding could be stopped sooner, and physiology and cell integrity preserved, these patients could survive to lead normal, healthy lives. Trauma hemorrhage therefore represents one of the greatest challenges and opportunities in medicine. In this issue of Science Translational Medicine, Chan et al. report on a new bioengineered polymer that circulates innocuously throughout the body and then, at the site of injury, cross-links fbrin to strengthen blood clots, reducing bleeding and improving survival in animals (1). THE BLEEDING OBVIOUS Disordered clotting is a central component of the pathophysiology of trauma hemorrhage and has become a subject of intense interest in recent years. Several patterns of coagulopathy are thought to coexist in trauma patients, although they remain incompletely described, and the drivers and mechanisms remain uncertain. Trauma itself appears to induce a coagulopathic state or states, as part of a maladaptive response to massive tissue damage and profound shock. Subsequently, resuscitation by use of fuids or blood products induces new forms of coagulopathy that exacerbate bleeding and attempts to restore hemostasis (2). Developing new therapeutics and strategies for the management of this multifactorial trauma-induced coagulopathy requires a holistic view of this dynamic complex system. At any time, hemostasis is a balance Centre for Trauma Sciences, Queen Mary University of London, London E1 4NS, UK. E-mail: [email protected]
of procoagulant factors forming clots, anticoagulant factors reducing the propensity to clot, and fbrinolytic factors limiting and clearing clots. ese factors are located in the plasma space, in cellular components of blood, and in the vessel wall. e hemostatic system must form a resilient clot that is
Risks of clotting intervention • Distant organ dysfunction • Microvascular thrombosis • Systemic infammation • Potential thromboembolism (for example, deep vein thrombosis or pulmonary embolism)
limited to the site of injury and that doesn’t propagate or embolize (obstruct the vessel). Importantly, the process must not generate a systemic hypercoagulable state, which might lead to organ dysfunction, arterial ischemia, or venous thromboembolism. Normally, the body is able to respond exquisitely to injury, forming appropriately localized clots regardless of whether the injury is a paper cut, a broken leg, or a bruised spleen. Modern trauma patients survive injuries that exceed the body’s hemostatic capacity. Coagulation changes that would normally be protective become excessive, maladaptive, or counterproductive. For example, with moderate injury and mild blood loss, the body generates a mildly anticoagulant, fbrinolytic state to avoid clotting in vessels and organs that are experiencing low blood fow. However, in massive injury and shock, this response is magnifed, and the body appears to become systemically anticoagulated and hyperfbrinolytic (3). is leads to weak clots that are rapidly cleared, and increased bleeding from injury sites and attempts at surgical
Trauma clot
Normal clot
Alternative targets • Increase factor substrate • Inhibit anticoagulation • Activate or bypass fbrin pathway • Inhibit fbrinolysis
Stabilize and strengthen clot (Chan et al.) Polymer Fibrin-binding peptide (FBP)
PolySTAT
Fibrin Endothelium
Activated platelets
Subendothelium
Dysfunctional platelets
Fig. 1. Designer clotting. Normal clots comprise a plug of activated platelets covered by a strong cross-linked fibrin network. In trauma, however, the clot may have dysfunctional platelets, with less fibrin, owing to reduced production, increased anticoagulation factors, and susceptibility to fibrinolysis. Chan et al. designed a new polymer-based approach to strengthen and stabilize the existing clot after trauma by localizing at the site of injury, noncovalently cross-linking fibrin through fibrin-binding peptides, and rendering it resistant to enzymatic breakdown (1). Other designer approaches include increasing factor substrates, inhibiting anticoagulation, activating or bypassing the fibrin pathway, and inhibiting fibrinolysis. Each intervention carries its own set of risks, however, including organ dysfunction, thrombosis, and exacerbated inflammation. These risks must be weighed against the benefit of new therapeutics for trauma-induced coagulopathies. www.ScienceTranslationalMedicine.org 4 March 2015 Vol 7 Issue 277 277fs10
1
Downloaded from stm.sciencemag.org on March 20, 2015
FOCUS
repair. Further bleeding leads to consumption and loss of clotting factors, whereas resuscitation with fuids or blood products leads to dilution and complicates the hemostatic picture. Patients who survive are ofen lef with exhausted or down-regulated anticoagulant and fbrinolytic mechanisms, leading to prothrombotic states and associated complications. us, the same patient, at diferent times, may be hypercoagulable, hypocoagulable, hyperfbrinolytic, or hypofbrinolytic. Furthermore, because coagulation is a subcomponent of infammation, these changes may lead to systemic pro- or anti-infammatory states, which may themselves have pathophysiological consequences, such as organ dysfunction and immunosuppression (4). DESIGNER CLOTTING Targeting and development of novel therapeutic agents therefore requires a considered approach. e system naturally tries to restore balance, so targets must act on central components of the system. Interventions must increase clotting ability and resilience where needed, without increasing the risk of distant or excessive thrombosis. Most coagulation strategies revolve around restoring hemostatic potential; in other words, when levels of clotting factors are reduced, either through consumption or dilution, more substrates are added to restore hemostasis. is strategy primarily involves the replacement of clotting factors, such as fbrinogen and factors II and V, through the administration of blood components through plasma, cryoprecipitate, or platelet transfusions (5). Factor replacement has the theoretical advantage in that the therapeutics are inactive substrates and not active compounds; as such, they should be able to circulate innocuously, only activated at the site of injury through normal hemostatic processes. However, as inactive substrates they do not promote or enhance clotting. Active procoagulants, such as recombinant factor VIIa or factor VIII inhibitor bypassing activity (FEIBA), are appealing therapeutic options, but the risk of excessive or remote clot formation is high unless their action can be targeted and localized. Alternatively, modulating the clot control mechanisms (anticoagulation and fbrinolysis) is an attractive target for novel therapeutics, and clinical trials of an antifbrinolytic agent, tranexamic acid, showed a signifcant reduction in mortality with early administration (6). However, systemic
modulation of these control pathways may result in remote thrombosis or exacerbate organ injury. Additionally, because these pathways are intimately linked with infammatory mechanisms, modulation may have benefcial anti-infammatory—or harmful pro-infammatory—efects. One strategy to combat bleeding is to strengthen a clot that has already started to form by making it inherently stronger or more resilient to shear stresses or fbrinolysis. To this end, Chan et al. manufactured a polymer that noncovalently cross-links fbrin monomers—similar to the body’s endogenous factor XIII or platelets—to form a fbrin network resistant to breakdown (Fig. 1). e transglutaminase factor XIIIa (FXIIIa) stabilizes the clot by enhancing the cross-linking of fbrin monomers. e authors’ polymer, named PolySTAT, mimicked FXIIIa-mediated fbrin stabilization because it contained multiple fbrin-binding domains on a (hydroxyethyl)methacrylate (HEMA) and N-hydroxysuccinimide methacrylate backbone; once polymerized, these components are safe in people. PolySTAT showed a high specifcity for fbrin but not other clotting components, such as fbrinogen or other plasma proteins. e formed fbrin-PolySTAT network was resistant to cleavage by the enzyme plasmin, thus reducing fbrinolysis. In a rodent model of hemorrhage from a femoral artery wound, PolySTAT reduced blood loss, abolished rebleeding at the injury site, and increased survival—even when compared with recombinant activated factor XIII (1). is fbrin-targeted approach to hemostasis, which acts downstream of thrombin generation, may be a safer alternative to active procoagulants by avoiding undesired thrombotic events. is approach is attractive because theoretically, it should be specifcally localized to the site of injury where fbrin monomers are being produced and form a sturdy clot while minimizing distant adverse events. Other groups have used such strategies, targeting diferent fbrin binding sites or building alternative bridges, using short chain peptides or nanoparticles (7). Efcacy of the localized PolySTAT efect described by Chan et al. may be improved. Bioengineering techniques can localize therapeutics to exposed subendothelium or to platelet surfaces. Recombinant factor VIIa, for example, has been targeted at the subendothelium, which is exposed after injury. It subsequently emerged that the majority of factor VII activation actually
occurs in a thrombin burst on the surface of platelets. us, factor VIIa has been reengineered to target the platelet membrane, although this compound has not yet entered clinical trials (8). Of particular interest, the microenvironment within a clot is very diferent from the systemic environment. Because active factor concentrations are orders of magnitude higher within clots, diferent pathways become more dominant. For example, one inhibitor of fbrinolysis, TAFI (thrombin-activatable fbrinolysis inhibitor), may only be clinically relevant in the high-thrombin environment generated by a factor XI feedback look inside a clot (9). Other intraclot pathways may represent targets for designer therapeutics and could be combined with the PolySTAT technology to produce a strong, resilient designer clot, formed rapidly only at the site of injury (Fig. 1). KNOW THY COAGULOPATHY, KNOW THY PATIENT Developing a targeted agent such as PolySTAT (1) is only one step in successful translation into clinical use. Drugs need to survive the rigors of the emergency environment. ose aimed at immediate intervention need to be deliverable at the roadside, in an ambulance, or on the battlefeld. Ideally, they must be stable over a wide range of temperatures and exist in small, easily transportable vials that are easy to dose and administer. eir efect must be easily monitored and have either an extremely safe effect profle or a short half-life allowing for termination or redosing as required. More fundamentally, there must be a clear understanding of which specifc coagulopathies the drug is efective for and in which it is safe (though, perhaps not efective). ese coagulopathies must be readily identifable, either through clinically relevant pointof-care tests or from patient physiology or injury characteristics. e narrower the safe indication for the therapeutic, the more important patient selection becomes. is is especially the case in designing clinical trials for efcacy and regulatory approval. If a targeted patient population cannot be rapidly and easily identifed, large subject numbers are required, and efect size will be diluted or adverse efects increased. is has been a clear issue of previous clinical trials of hemostatic therapeutics in trauma (10). Promising agents have been lost owing to failure to understand the multiple coagulopathies that can exist in a trauma patient,
www.ScienceTranslationalMedicine.org 4 March 2015 Vol 7 Issue 277 277fs10
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Downloaded from stm.sciencemag.org on March 20, 2015
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to understand positive or negative efect on each of these, and to design trials that individualize care to these patients by using appropriate diagnostic tools. ese are the challenges PolySTAT will face moving from current proof of concept in rodents through to clinical use. Future drug design and development can be supported with translational approaches to personalized medicine with new point-of-care diagnostic devices and decision-support tools. Trauma hemorrhage represents a major opportunity for translational medicine. e potential number of lives saved on a global scale is enormous. New discoveries in the pathophysiology of the disease are revealing new opportunities for therapeutics and diagnostics. e feld is challenging, owing to the complexity of the systems involved, disease processes, and the clinical environment. Ultimately, success will require the combined eforts of systems biology, experimental medicine, bioengineering, medicinal chemistry, translational therapeutics, and specialist clinical trial units working at an international scale to develop new interventions and bring them to clinical practice and to the bleeding casualty.
REFERENCES AND NOTES 1. L. W. Chan, X. Wang, H. Wei, L. D. Pozzo, N. J. White, S. H. Pun, A synthetic fibrin cross-linking polymer for modulating clot properties and inducing hemostasis. Sci. Transl. Med. 7, 277ra29 (2015). 2. D. Frith, K. Brohi, The pathophysiology of traumainduced coagulopathy. Curr. Opin. Crit. Care 18, 631–636 (2012). 3. K. Brohi, M. J. Cohen, M. T. Ganter, M. J. Schultz, M. Levi, R. C. Mackersie, J. F. Pittet, Acute coagulopathy of trauma: Hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J. Trauma 64, 1211–1217 (2008). 4. E. L. Vanzant, C. M. Lopez, T. Ozrazgat-Baslanti, R. Ungaro, R. Davis, A. G. Cuenca, L. F. Gentile, D. C. Nacionales, A. L. Cuenca, A. Bihorac, C. Leeuwenburgh, J. Lanz, H. V. Baker, B. McKinley, L. L. Moldawer, F. A. Moore, P. A. Efron, Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J. Trauma Acute Care Surg. 76, 21–29 (2014). 5. I. Raza, R. Davenport, C. Rourke, S. Platton, J. Manson, C. Spoors, S. Khan, H. D. De’Ath, S. Allard, D. P. Hart, K. J. Pasi, B. J. Hunt, S. Stanworth, P. K. MacCallum, K. Brohi, The incidence and magnitude of fibrinolytic activation in trauma patients. J. Thromb. Haemost. 11, 307–314 (2013). 6. H. Shakur, I. Roberts, R. Bautista, J. Caballero, T. Coats, Y. Dewan, H. El-Sayed, T. Gogichaishvili, S. Gupta, J. Herrera, B. Hunt, P. Iribhogbe, M. Izurieta, H. Khamis, E. Komolafe, M. A. Marrero, J. Mejía-Mantilla, J. Miranda, C. Morales, O. Olaomi, F. Olldashi, P. Perel, R. Peto, P. V. Ramana, R. R. Ravi, S. Yutthakasemsunt, CRASH-2 trial collaborators, Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 376, 23–32 (2010).
7. M. M. Lashof-Sullivan, E. Shoffstall, K. T. Atkins, N. Keane, C. Bir, P. VandeVord, E. B. Lavik, Intravenously administered nanoparticles increase survival following blast trauma. Proc. Natl. Acad. Sci. U.S.A. 111, 10293–10298 (2014). 8. J. N. Mahlangu, M. J. Coetzee, M. Laffan, J. Windyga, T. T. Yee, J. Schroeder, J. Haaning, J. E. Siegel, G. Lemm, Phase I, randomized, double-blind, placebo-controlled, singledose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia. J. Thromb. Haemost. 10, 773–780 (2012). 9. C. Carrieri, R. Galasso, F. Semeraro, C. T. Ammollo, N. Semeraro, M. Colucci, The role of thrombin activatable fibrinolysis inhibitor and factor XI in platelet-mediated fibrinolysis resistance: A thromboelastographic study in whole blood. J. Thromb. Haemost. 9, 154–162 (2011). 10. S. B. Rizoli, K. D. Boffard, B. Riou, B. Warren, P. Iau, Y. Kluger, R. Rossaint, M. Tillinger, NovoSeven Trauma Study Group, Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: Subgroup analysis from two randomized trials. Crit. Care 10, R178 (2006). Competing interests: K.B. has previously consulted for AstraZeneca, Novo Nordisk, CSL Behring, and Haemonetics and received unrestricted grant funding from AstraZeneca, Octapharma, Haemonetics, and TEM International in the field of trauma haemostasis diagnostics and therapeutics.
10.1126/scitranslmed.aaa6555 Citation: K. Brohi, Make the bleeding stop. Sci. Transl. Med. 7, 277fs10 (2015).
www.ScienceTranslationalMedicine.org 4 March 2015 Vol 7 Issue 277 277fs10
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Downloaded from stm.sciencemag.org on March 20, 2015
FOCUS
Make the bleeding stop Karim Brohi A synthetic polymer that cross-links fbrin shows promise in the management of hemorrhage (Chan et al., this issue).
CREDIT: V. ALTOUNIAN/SCIENCE TRANSLATIONAL MEDICINE
Tirty people will bleed to death from their injuries while you read this article. Trauma hemorrhage is one of the world’s biggest killers, responsible for more than 2 million deaths every year. Deaths occur quickly, from exsanguination or failure to control bleeding, and late from the complications of profound shock, including multiple organ failure and sepsis. Casualties with massive hemorrhage approach a 50% mortality rate, even if the patients reach a hospital. Yet, the majority of these deaths are potentially preventable. If bleeding could be stopped sooner, and physiology and cell integrity preserved, these patients could survive to lead normal, healthy lives. Trauma hemorrhage therefore represents one of the greatest challenges and opportunities in medicine. In this issue of Science Translational Medicine, Chan et al. report on a new bioengineered polymer that circulates innocuously throughout the body and then, at the site of injury, cross-links fbrin to strengthen blood clots, reducing bleeding and improving survival in animals (1). THE BLEEDING OBVIOUS Disordered clotting is a central component of the pathophysiology of trauma hemorrhage and has become a subject of intense interest in recent years. Several patterns of coagulopathy are thought to coexist in trauma patients, although they remain incompletely described, and the drivers and mechanisms remain uncertain. Trauma itself appears to induce a coagulopathic state or states, as part of a maladaptive response to massive tissue damage and profound shock. Subsequently, resuscitation by use of fuids or blood products induces new forms of coagulopathy that exacerbate bleeding and attempts to restore hemostasis (2). Developing new therapeutics and strategies for the management of this multifactorial trauma-induced coagulopathy requires a holistic view of this dynamic complex system. At any time, hemostasis is a balance Centre for Trauma Sciences, Queen Mary University of London, London E1 4NS, UK. E-mail: [email protected]
of procoagulant factors forming clots, anticoagulant factors reducing the propensity to clot, and fbrinolytic factors limiting and clearing clots. ese factors are located in the plasma space, in cellular components of blood, and in the vessel wall. e hemostatic system must form a resilient clot that is
Risks of clotting intervention • Distant organ dysfunction • Microvascular thrombosis • Systemic infammation • Potential thromboembolism (for example, deep vein thrombosis or pulmonary embolism)
limited to the site of injury and that doesn’t propagate or embolize (obstruct the vessel). Importantly, the process must not generate a systemic hypercoagulable state, which might lead to organ dysfunction, arterial ischemia, or venous thromboembolism. Normally, the body is able to respond exquisitely to injury, forming appropriately localized clots regardless of whether the injury is a paper cut, a broken leg, or a bruised spleen. Modern trauma patients survive injuries that exceed the body’s hemostatic capacity. Coagulation changes that would normally be protective become excessive, maladaptive, or counterproductive. For example, with moderate injury and mild blood loss, the body generates a mildly anticoagulant, fbrinolytic state to avoid clotting in vessels and organs that are experiencing low blood fow. However, in massive injury and shock, this response is magnifed, and the body appears to become systemically anticoagulated and hyperfbrinolytic (3). is leads to weak clots that are rapidly cleared, and increased bleeding from injury sites and attempts at surgical
Trauma clot
Normal clot
Alternative targets • Increase factor substrate • Inhibit anticoagulation • Activate or bypass fbrin pathway • Inhibit fbrinolysis
Stabilize and strengthen clot (Chan et al.) Polymer Fibrin-binding peptide (FBP)
PolySTAT
Fibrin Endothelium
Activated platelets
Subendothelium
Dysfunctional platelets
Fig. 1. Designer clotting. Normal clots comprise a plug of activated platelets covered by a strong cross-linked fibrin network. In trauma, however, the clot may have dysfunctional platelets, with less fibrin, owing to reduced production, increased anticoagulation factors, and susceptibility to fibrinolysis. Chan et al. designed a new polymer-based approach to strengthen and stabilize the existing clot after trauma by localizing at the site of injury, noncovalently cross-linking fibrin through fibrin-binding peptides, and rendering it resistant to enzymatic breakdown (1). Other designer approaches include increasing factor substrates, inhibiting anticoagulation, activating or bypassing the fibrin pathway, and inhibiting fibrinolysis. Each intervention carries its own set of risks, however, including organ dysfunction, thrombosis, and exacerbated inflammation. These risks must be weighed against the benefit of new therapeutics for trauma-induced coagulopathies. www.ScienceTranslationalMedicine.org 4 March 2015 Vol 7 Issue 277 277fs10
1
Downloaded from stm.sciencemag.org on March 20, 2015
FOCUS
repair. Further bleeding leads to consumption and loss of clotting factors, whereas resuscitation with fuids or blood products leads to dilution and complicates the hemostatic picture. Patients who survive are ofen lef with exhausted or down-regulated anticoagulant and fbrinolytic mechanisms, leading to prothrombotic states and associated complications. us, the same patient, at diferent times, may be hypercoagulable, hypocoagulable, hyperfbrinolytic, or hypofbrinolytic. Furthermore, because coagulation is a subcomponent of infammation, these changes may lead to systemic pro- or anti-infammatory states, which may themselves have pathophysiological consequences, such as organ dysfunction and immunosuppression (4). DESIGNER CLOTTING Targeting and development of novel therapeutic agents therefore requires a considered approach. e system naturally tries to restore balance, so targets must act on central components of the system. Interventions must increase clotting ability and resilience where needed, without increasing the risk of distant or excessive thrombosis. Most coagulation strategies revolve around restoring hemostatic potential; in other words, when levels of clotting factors are reduced, either through consumption or dilution, more substrates are added to restore hemostasis. is strategy primarily involves the replacement of clotting factors, such as fbrinogen and factors II and V, through the administration of blood components through plasma, cryoprecipitate, or platelet transfusions (5). Factor replacement has the theoretical advantage in that the therapeutics are inactive substrates and not active compounds; as such, they should be able to circulate innocuously, only activated at the site of injury through normal hemostatic processes. However, as inactive substrates they do not promote or enhance clotting. Active procoagulants, such as recombinant factor VIIa or factor VIII inhibitor bypassing activity (FEIBA), are appealing therapeutic options, but the risk of excessive or remote clot formation is high unless their action can be targeted and localized. Alternatively, modulating the clot control mechanisms (anticoagulation and fbrinolysis) is an attractive target for novel therapeutics, and clinical trials of an antifbrinolytic agent, tranexamic acid, showed a signifcant reduction in mortality with early administration (6). However, systemic
modulation of these control pathways may result in remote thrombosis or exacerbate organ injury. Additionally, because these pathways are intimately linked with infammatory mechanisms, modulation may have benefcial anti-infammatory—or harmful pro-infammatory—efects. One strategy to combat bleeding is to strengthen a clot that has already started to form by making it inherently stronger or more resilient to shear stresses or fbrinolysis. To this end, Chan et al. manufactured a polymer that noncovalently cross-links fbrin monomers—similar to the body’s endogenous factor XIII or platelets—to form a fbrin network resistant to breakdown (Fig. 1). e transglutaminase factor XIIIa (FXIIIa) stabilizes the clot by enhancing the cross-linking of fbrin monomers. e authors’ polymer, named PolySTAT, mimicked FXIIIa-mediated fbrin stabilization because it contained multiple fbrin-binding domains on a (hydroxyethyl)methacrylate (HEMA) and N-hydroxysuccinimide methacrylate backbone; once polymerized, these components are safe in people. PolySTAT showed a high specifcity for fbrin but not other clotting components, such as fbrinogen or other plasma proteins. e formed fbrin-PolySTAT network was resistant to cleavage by the enzyme plasmin, thus reducing fbrinolysis. In a rodent model of hemorrhage from a femoral artery wound, PolySTAT reduced blood loss, abolished rebleeding at the injury site, and increased survival—even when compared with recombinant activated factor XIII (1). is fbrin-targeted approach to hemostasis, which acts downstream of thrombin generation, may be a safer alternative to active procoagulants by avoiding undesired thrombotic events. is approach is attractive because theoretically, it should be specifcally localized to the site of injury where fbrin monomers are being produced and form a sturdy clot while minimizing distant adverse events. Other groups have used such strategies, targeting diferent fbrin binding sites or building alternative bridges, using short chain peptides or nanoparticles (7). Efcacy of the localized PolySTAT efect described by Chan et al. may be improved. Bioengineering techniques can localize therapeutics to exposed subendothelium or to platelet surfaces. Recombinant factor VIIa, for example, has been targeted at the subendothelium, which is exposed after injury. It subsequently emerged that the majority of factor VII activation actually
occurs in a thrombin burst on the surface of platelets. us, factor VIIa has been reengineered to target the platelet membrane, although this compound has not yet entered clinical trials (8). Of particular interest, the microenvironment within a clot is very diferent from the systemic environment. Because active factor concentrations are orders of magnitude higher within clots, diferent pathways become more dominant. For example, one inhibitor of fbrinolysis, TAFI (thrombin-activatable fbrinolysis inhibitor), may only be clinically relevant in the high-thrombin environment generated by a factor XI feedback look inside a clot (9). Other intraclot pathways may represent targets for designer therapeutics and could be combined with the PolySTAT technology to produce a strong, resilient designer clot, formed rapidly only at the site of injury (Fig. 1). KNOW THY COAGULOPATHY, KNOW THY PATIENT Developing a targeted agent such as PolySTAT (1) is only one step in successful translation into clinical use. Drugs need to survive the rigors of the emergency environment. ose aimed at immediate intervention need to be deliverable at the roadside, in an ambulance, or on the battlefeld. Ideally, they must be stable over a wide range of temperatures and exist in small, easily transportable vials that are easy to dose and administer. eir efect must be easily monitored and have either an extremely safe effect profle or a short half-life allowing for termination or redosing as required. More fundamentally, there must be a clear understanding of which specifc coagulopathies the drug is efective for and in which it is safe (though, perhaps not efective). ese coagulopathies must be readily identifable, either through clinically relevant pointof-care tests or from patient physiology or injury characteristics. e narrower the safe indication for the therapeutic, the more important patient selection becomes. is is especially the case in designing clinical trials for efcacy and regulatory approval. If a targeted patient population cannot be rapidly and easily identifed, large subject numbers are required, and efect size will be diluted or adverse efects increased. is has been a clear issue of previous clinical trials of hemostatic therapeutics in trauma (10). Promising agents have been lost owing to failure to understand the multiple coagulopathies that can exist in a trauma patient,
www.ScienceTranslationalMedicine.org 4 March 2015 Vol 7 Issue 277 277fs10
2
Downloaded from stm.sciencemag.org on March 20, 2015
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to understand positive or negative efect on each of these, and to design trials that individualize care to these patients by using appropriate diagnostic tools. ese are the challenges PolySTAT will face moving from current proof of concept in rodents through to clinical use. Future drug design and development can be supported with translational approaches to personalized medicine with new point-of-care diagnostic devices and decision-support tools. Trauma hemorrhage represents a major opportunity for translational medicine. e potential number of lives saved on a global scale is enormous. New discoveries in the pathophysiology of the disease are revealing new opportunities for therapeutics and diagnostics. e feld is challenging, owing to the complexity of the systems involved, disease processes, and the clinical environment. Ultimately, success will require the combined eforts of systems biology, experimental medicine, bioengineering, medicinal chemistry, translational therapeutics, and specialist clinical trial units working at an international scale to develop new interventions and bring them to clinical practice and to the bleeding casualty.
REFERENCES AND NOTES 1. L. W. Chan, X. Wang, H. Wei, L. D. Pozzo, N. J. White, S. H. Pun, A synthetic fibrin cross-linking polymer for modulating clot properties and inducing hemostasis. Sci. Transl. Med. 7, 277ra29 (2015). 2. D. Frith, K. Brohi, The pathophysiology of traumainduced coagulopathy. Curr. Opin. Crit. Care 18, 631–636 (2012). 3. K. Brohi, M. J. Cohen, M. T. Ganter, M. J. Schultz, M. Levi, R. C. Mackersie, J. F. Pittet, Acute coagulopathy of trauma: Hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J. Trauma 64, 1211–1217 (2008). 4. E. L. Vanzant, C. M. Lopez, T. Ozrazgat-Baslanti, R. Ungaro, R. Davis, A. G. Cuenca, L. F. Gentile, D. C. Nacionales, A. L. Cuenca, A. Bihorac, C. Leeuwenburgh, J. Lanz, H. V. Baker, B. McKinley, L. L. Moldawer, F. A. Moore, P. A. Efron, Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J. Trauma Acute Care Surg. 76, 21–29 (2014). 5. I. Raza, R. Davenport, C. Rourke, S. Platton, J. Manson, C. Spoors, S. Khan, H. D. De’Ath, S. Allard, D. P. Hart, K. J. Pasi, B. J. Hunt, S. Stanworth, P. K. MacCallum, K. Brohi, The incidence and magnitude of fibrinolytic activation in trauma patients. J. Thromb. Haemost. 11, 307–314 (2013). 6. H. Shakur, I. Roberts, R. Bautista, J. Caballero, T. Coats, Y. Dewan, H. El-Sayed, T. Gogichaishvili, S. Gupta, J. Herrera, B. Hunt, P. Iribhogbe, M. Izurieta, H. Khamis, E. Komolafe, M. A. Marrero, J. Mejía-Mantilla, J. Miranda, C. Morales, O. Olaomi, F. Olldashi, P. Perel, R. Peto, P. V. Ramana, R. R. Ravi, S. Yutthakasemsunt, CRASH-2 trial collaborators, Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 376, 23–32 (2010).
7. M. M. Lashof-Sullivan, E. Shoffstall, K. T. Atkins, N. Keane, C. Bir, P. VandeVord, E. B. Lavik, Intravenously administered nanoparticles increase survival following blast trauma. Proc. Natl. Acad. Sci. U.S.A. 111, 10293–10298 (2014). 8. J. N. Mahlangu, M. J. Coetzee, M. Laffan, J. Windyga, T. T. Yee, J. Schroeder, J. Haaning, J. E. Siegel, G. Lemm, Phase I, randomized, double-blind, placebo-controlled, singledose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia. J. Thromb. Haemost. 10, 773–780 (2012). 9. C. Carrieri, R. Galasso, F. Semeraro, C. T. Ammollo, N. Semeraro, M. Colucci, The role of thrombin activatable fibrinolysis inhibitor and factor XI in platelet-mediated fibrinolysis resistance: A thromboelastographic study in whole blood. J. Thromb. Haemost. 9, 154–162 (2011). 10. S. B. Rizoli, K. D. Boffard, B. Riou, B. Warren, P. Iau, Y. Kluger, R. Rossaint, M. Tillinger, NovoSeven Trauma Study Group, Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: Subgroup analysis from two randomized trials. Crit. Care 10, R178 (2006). Competing interests: K.B. has previously consulted for AstraZeneca, Novo Nordisk, CSL Behring, and Haemonetics and received unrestricted grant funding from AstraZeneca, Octapharma, Haemonetics, and TEM International in the field of trauma haemostasis diagnostics and therapeutics.
10.1126/scitranslmed.aaa6555 Citation: K. Brohi, Make the bleeding stop. Sci. Transl. Med. 7, 277fs10 (2015).
www.ScienceTranslationalMedicine.org 4 March 2015 Vol 7 Issue 277 277fs10
3
Downloaded from stm.sciencemag.org on March 20, 2015
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