Thrombosis Research 134 (2014) 535–536
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
Monitoring coagulopathies in fluid resuscitation for trauma or surgery Keywords: Fluid resuscitation Hemodilution Clot strength Fractal dimension
Trauma is a global health problem that accounts for about 10,000 deaths per day and affects people of all socioeconomic status. It is the major cause of death in individuals less than 35 years of age, with uncontrolled hemorrhage representing the main cause of preventable deaths following both civilian and military trauma [1]. Many of the responses of the body to trauma complicate the treatment of hemorrhage and contribute to the associated high mortality [2,3]. Dysfunctional hemostasis is present in a significant fraction of severely injured trauma patients and is associated with a four-fold increase in mortality, regardless of injury severity [4]. For both trauma and some forms of surgery, resuscitation fluids are commonly administered when blood products are unavailable and direct hemorrhage control is delayed [5,6]. The goals of resuscitation in hemorrhagic shock are maintaining tissue oxygenation and attaining control of bleeding. However, recent studies have shown that some forms of fluid resuscitation can actually exacerbate injury caused by hemorrhagic shock, and the type, quantity, and timing of fluid used for resuscitation is important [5,6]. As a result, research to develop better methods of resuscitation is ongoing. In the initial management of hemorrhage prior to component replacement or definitive hemorrhage control, the clinician will use either crystalloid or colloid to maintain intravascular volume. Both crystalloids and colloids have dilution effects, which can lead to a reduction in clot quality and hence bleeding. Furthermore, although crystalloids have a purely dilutional effect, colloids have both a dilutional and intrinsic effect due to their individual chemical structures, which has an additive effect on reducing clot quality. Managing hemorrhage therefore is a subtle balance between the administration of fluid to maintain tissue perfusion against the detrimental effect that these intravenous fluids have on clot quality and hemostasis. Although it can sometimes seem that we know nearly everything about all aspects of clotting, it may be shocking to realize that we know so little about the effects of trauma and hemodilution on the clotting system. One of the major problems in studying the many clinical aspects of hemostasis and thrombosis is that simple and accurate methods to quantify clot strength and to assess overall clot quality are severely lacking [7–9]. What is required in the case of trauma and fluid resuscitation is a dynamic test that not only measures the dilutional effects of the fluids, but also assesses and quantifies how their intrinsic effects alter clot quality and bleeding risks.
http://dx.doi.org/10.1016/j.thromres.2014.07.017 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Thromboelastography has been used to identify defective clotting by measurement of prolongation of clotting time and decreased clot maximal strength [10,11]. However, this method does not allow separation of the effects of defects in platelets versus fibrin. Both clot strength and platelet contractile force have been measured with another instrument in a swine model of traumatic shock [12–15]. A novel structural biomarker of clot quality and its specific application to hemodilution is described in a paper in this issue of Thrombosis Research [16]. This approach may also be useful to monitor patients with trauma and during fluid resuscitation, as well as to help understand these conditions. A rheological method has been developed by this group to determine the clotting time or gel point more accurately than other commonly used approaches. More significantly, this approach allows the determination of the mechanical or viscoelastic properties of the incipient clot at the instant of formation, both the clot strength or G’GP and clot microstructure (df or fractal dimension) [17–19]. Furthermore, these studies are carried out with unadulterated whole blood, both providing simplicity in use and avoiding potential complications of common anticoagulants. They use Fourier transform mechanical spectroscopy, a technique involving oscillatory deformations over a range of frequencies, which is especially suited to detect the gel point because of a fundamental difference between liquids and solids: the ratio of the viscous and elastic components of the complex modulus decreases with frequency for a liquid but increases for a solid. In these studies, the fractal dimension, which is a measure of how completely a fractal, or selfsimilar pattern, appears to fill space as one goes down to finer and finer spatial scales, is used as an indication of the network complexity. At the gel point, the branching clot network establishes sufficient connectivity to become sample-spanning, conferring the properties of a solid on the system. In the new study in this issue of Thrombosis Research, the gel point, clot strength, and fractal dimension were measured to investigate the effects of progressive hemodilution by a crystalloid fluid commonly used for resuscitation, isotonic saline [16]. While the usual rate-based measures of clotting such as the PT and APTT did not show significant differences until 40% dilution, the clot microstructure (fractal dimension or df) was significantly different at a dilution of 20%. Furthermore, computational simulation was used to illustrate the relationship between clot microstructure (df) and mass incorporated into the structure during progressive dilution. The role of the incipient clot microstructure (as represented by df) was investigated as a template for further clot development by comparing it to images of the mature clot using a type of scanning electron microscopy called helium ion microscopy. In these electron micrographs, there were differences in clot structure that were quantified by measurements of decreased fiber diameter. In summary, this paper quantifies the effects of hemodilution by isotonic saline on clot structure and strength and provides new insights into potential mechanisms.
536
Editorial
Methods to assess the coagulation status of trauma patients both initially and during fluid resuscitation are necessary to investigate the pathophysiology that may contribute to the development of coagulopathies. Furthermore, it is important to identify biomarkers predictive of clinical outcomes. This study may be an significant advance in this effort. Conflict of Interest Statement The author has no conflict of interest. References [1] Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006;60:S3–S11. [2] Shaz BH, Winkler AM, James AB, Hillyer CD, MacLeod JB. Pathophysiology of early trauma-induced coagulopathy: emerging evidence for hemodilution and coagulation factor depletion. J Trauma 2011;70:1401–7. [3] Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008;65:748–54. [4] MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003;55:39–44. [5] Harris T, Thomas GO, Brohi K. Early fluid resuscitation in severe trauma. BMJ 2012;345:e5752. [6] Santry HP, Alam HB. Fluid resuscitation: past, present, and the future. Shock 2010;33:229–41. [7] Parr MJ, Bouillon B, Brohi K, Dutton RP, Hauser CJ, Hess JR, et al. Traumatic coagulopathy: where are the good experimental models? J Trauma 2008;65:766–71. [8] Evans PA, Hawkins K, Lawrence M, Barrow MS, Williams PR, Williams RL. Studies of whole blood coagulation by oscillatory shear, thromboelastography and free oscillation rheometry. Clin Hemorheol Microcirc 2008;38:267–77. [9] Evans PA, Hawkins K, Lawrence M, Williams RL, Barrow MS, Thirumalai N, et al. Rheometry and associated techniques for blood coagulation studies. Med Eng Phys 2008;30:671–9. [10] Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma 1997;42:716–20 [discussion 20–2].
[11] Rugeri L, Levrat A, David JS, Delecroix E, Floccard B, Gros A, et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 2007;5:289–95. [12] White NJ, Martin EJ, Brophy DF, Ward KR. Examining platelet-fibrin interactions during traumatic shock in a swine model using platelet contractile force and clot elastic modulus. Blood Coagul Fibrinolysis 2011;22:379–87. [13] White NJ, Leong BS, Brueckner J, Martin EJ, Brophy DF, Peberdy MA, et al. Coagulopathy during cardiac arrest and resuscitation in a swine model of electrically induced ventricular fibrillation. Resuscitation 2011;82:925–31. [14] White NJ, Martin EJ, Shin Y, Brophy DF, Diegelmann RF, Ward KR. Systemic central venous oxygen saturation is associated with clot strength during traumatic hemorrhagic shock: A preclinical observational model. Scand J Trauma Resusc Emerg Med 2010;18:64. [15] White NJ, Martin EJ, Brophy DF, Ward KR. Coagulopathy and traumatic shock: characterizing hemostatic function during the critical period prior to fluid resuscitation. Resuscitation 2010;81:111–6. [16] Lawrence M, Kumar S, Hawkins K, Boden S, Rutt H, Mills G, et al. A new structural biomarker that quantifies and predicts changes in clot strength and quality in a model of progressive haemodilution. Thromb Res 2014;134:488–94 (in this issue). [17] Evans PA, Hawkins K, Morris RH, Thirumalai N, Munro R, Wakeman L, et al. Gel point and fractal microstructure of incipient blood clots are significant new markers of hemostasis for healthy and anticoagulated blood. Blood 2010;116: 3341–6. [18] Williams PR, Hawkins K, Wright C, Evans A, Simpkin H, Barrow MS, et al. Rheometrical and computational studies of blood viscoelasticity during coagulation. Clin Hemorheol Microcirc 2006;35:123–7. [19] Weisel JW. Ta panta rei. Blood 2010;116:3123–4.
John W. Weisel Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104–6058 Tel.: +1 215 898 3573. E-mail address: [email protected]. 23 June 2014
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Editorial
Monitoring coagulopathies in fluid resuscitation for trauma or surgery Keywords: Fluid resuscitation Hemodilution Clot strength Fractal dimension
Trauma is a global health problem that accounts for about 10,000 deaths per day and affects people of all socioeconomic status. It is the major cause of death in individuals less than 35 years of age, with uncontrolled hemorrhage representing the main cause of preventable deaths following both civilian and military trauma [1]. Many of the responses of the body to trauma complicate the treatment of hemorrhage and contribute to the associated high mortality [2,3]. Dysfunctional hemostasis is present in a significant fraction of severely injured trauma patients and is associated with a four-fold increase in mortality, regardless of injury severity [4]. For both trauma and some forms of surgery, resuscitation fluids are commonly administered when blood products are unavailable and direct hemorrhage control is delayed [5,6]. The goals of resuscitation in hemorrhagic shock are maintaining tissue oxygenation and attaining control of bleeding. However, recent studies have shown that some forms of fluid resuscitation can actually exacerbate injury caused by hemorrhagic shock, and the type, quantity, and timing of fluid used for resuscitation is important [5,6]. As a result, research to develop better methods of resuscitation is ongoing. In the initial management of hemorrhage prior to component replacement or definitive hemorrhage control, the clinician will use either crystalloid or colloid to maintain intravascular volume. Both crystalloids and colloids have dilution effects, which can lead to a reduction in clot quality and hence bleeding. Furthermore, although crystalloids have a purely dilutional effect, colloids have both a dilutional and intrinsic effect due to their individual chemical structures, which has an additive effect on reducing clot quality. Managing hemorrhage therefore is a subtle balance between the administration of fluid to maintain tissue perfusion against the detrimental effect that these intravenous fluids have on clot quality and hemostasis. Although it can sometimes seem that we know nearly everything about all aspects of clotting, it may be shocking to realize that we know so little about the effects of trauma and hemodilution on the clotting system. One of the major problems in studying the many clinical aspects of hemostasis and thrombosis is that simple and accurate methods to quantify clot strength and to assess overall clot quality are severely lacking [7–9]. What is required in the case of trauma and fluid resuscitation is a dynamic test that not only measures the dilutional effects of the fluids, but also assesses and quantifies how their intrinsic effects alter clot quality and bleeding risks.
http://dx.doi.org/10.1016/j.thromres.2014.07.017 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
Thromboelastography has been used to identify defective clotting by measurement of prolongation of clotting time and decreased clot maximal strength [10,11]. However, this method does not allow separation of the effects of defects in platelets versus fibrin. Both clot strength and platelet contractile force have been measured with another instrument in a swine model of traumatic shock [12–15]. A novel structural biomarker of clot quality and its specific application to hemodilution is described in a paper in this issue of Thrombosis Research [16]. This approach may also be useful to monitor patients with trauma and during fluid resuscitation, as well as to help understand these conditions. A rheological method has been developed by this group to determine the clotting time or gel point more accurately than other commonly used approaches. More significantly, this approach allows the determination of the mechanical or viscoelastic properties of the incipient clot at the instant of formation, both the clot strength or G’GP and clot microstructure (df or fractal dimension) [17–19]. Furthermore, these studies are carried out with unadulterated whole blood, both providing simplicity in use and avoiding potential complications of common anticoagulants. They use Fourier transform mechanical spectroscopy, a technique involving oscillatory deformations over a range of frequencies, which is especially suited to detect the gel point because of a fundamental difference between liquids and solids: the ratio of the viscous and elastic components of the complex modulus decreases with frequency for a liquid but increases for a solid. In these studies, the fractal dimension, which is a measure of how completely a fractal, or selfsimilar pattern, appears to fill space as one goes down to finer and finer spatial scales, is used as an indication of the network complexity. At the gel point, the branching clot network establishes sufficient connectivity to become sample-spanning, conferring the properties of a solid on the system. In the new study in this issue of Thrombosis Research, the gel point, clot strength, and fractal dimension were measured to investigate the effects of progressive hemodilution by a crystalloid fluid commonly used for resuscitation, isotonic saline [16]. While the usual rate-based measures of clotting such as the PT and APTT did not show significant differences until 40% dilution, the clot microstructure (fractal dimension or df) was significantly different at a dilution of 20%. Furthermore, computational simulation was used to illustrate the relationship between clot microstructure (df) and mass incorporated into the structure during progressive dilution. The role of the incipient clot microstructure (as represented by df) was investigated as a template for further clot development by comparing it to images of the mature clot using a type of scanning electron microscopy called helium ion microscopy. In these electron micrographs, there were differences in clot structure that were quantified by measurements of decreased fiber diameter. In summary, this paper quantifies the effects of hemodilution by isotonic saline on clot structure and strength and provides new insights into potential mechanisms.
536
Editorial
Methods to assess the coagulation status of trauma patients both initially and during fluid resuscitation are necessary to investigate the pathophysiology that may contribute to the development of coagulopathies. Furthermore, it is important to identify biomarkers predictive of clinical outcomes. This study may be an significant advance in this effort. Conflict of Interest Statement The author has no conflict of interest. References [1] Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006;60:S3–S11. [2] Shaz BH, Winkler AM, James AB, Hillyer CD, MacLeod JB. Pathophysiology of early trauma-induced coagulopathy: emerging evidence for hemodilution and coagulation factor depletion. J Trauma 2011;70:1401–7. [3] Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB, Kluger Y, et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008;65:748–54. [4] MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003;55:39–44. [5] Harris T, Thomas GO, Brohi K. Early fluid resuscitation in severe trauma. BMJ 2012;345:e5752. [6] Santry HP, Alam HB. Fluid resuscitation: past, present, and the future. Shock 2010;33:229–41. [7] Parr MJ, Bouillon B, Brohi K, Dutton RP, Hauser CJ, Hess JR, et al. Traumatic coagulopathy: where are the good experimental models? J Trauma 2008;65:766–71. [8] Evans PA, Hawkins K, Lawrence M, Barrow MS, Williams PR, Williams RL. Studies of whole blood coagulation by oscillatory shear, thromboelastography and free oscillation rheometry. Clin Hemorheol Microcirc 2008;38:267–77. [9] Evans PA, Hawkins K, Lawrence M, Williams RL, Barrow MS, Thirumalai N, et al. Rheometry and associated techniques for blood coagulation studies. Med Eng Phys 2008;30:671–9. [10] Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma 1997;42:716–20 [discussion 20–2].
[11] Rugeri L, Levrat A, David JS, Delecroix E, Floccard B, Gros A, et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 2007;5:289–95. [12] White NJ, Martin EJ, Brophy DF, Ward KR. Examining platelet-fibrin interactions during traumatic shock in a swine model using platelet contractile force and clot elastic modulus. Blood Coagul Fibrinolysis 2011;22:379–87. [13] White NJ, Leong BS, Brueckner J, Martin EJ, Brophy DF, Peberdy MA, et al. Coagulopathy during cardiac arrest and resuscitation in a swine model of electrically induced ventricular fibrillation. Resuscitation 2011;82:925–31. [14] White NJ, Martin EJ, Shin Y, Brophy DF, Diegelmann RF, Ward KR. Systemic central venous oxygen saturation is associated with clot strength during traumatic hemorrhagic shock: A preclinical observational model. Scand J Trauma Resusc Emerg Med 2010;18:64. [15] White NJ, Martin EJ, Brophy DF, Ward KR. Coagulopathy and traumatic shock: characterizing hemostatic function during the critical period prior to fluid resuscitation. Resuscitation 2010;81:111–6. [16] Lawrence M, Kumar S, Hawkins K, Boden S, Rutt H, Mills G, et al. A new structural biomarker that quantifies and predicts changes in clot strength and quality in a model of progressive haemodilution. Thromb Res 2014;134:488–94 (in this issue). [17] Evans PA, Hawkins K, Morris RH, Thirumalai N, Munro R, Wakeman L, et al. Gel point and fractal microstructure of incipient blood clots are significant new markers of hemostasis for healthy and anticoagulated blood. Blood 2010;116: 3341–6. [18] Williams PR, Hawkins K, Wright C, Evans A, Simpkin H, Barrow MS, et al. Rheometrical and computational studies of blood viscoelasticity during coagulation. Clin Hemorheol Microcirc 2006;35:123–7. [19] Weisel JW. Ta panta rei. Blood 2010;116:3123–4.
John W. Weisel Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104–6058 Tel.: +1 215 898 3573. E-mail address: [email protected]. 23 June 2014
