Ignite Creation Date:
2024-05-06 @ 9:47 AM
Last Modification Date:
2024-10-26 @ 12:20 PM
Study NCT ID:
NCT03077269
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-07-27
First Post:
2017-03-01
Brief Title:
Understanding Coagulation and Inflammation in Burns
Sponsor:
University of Rochester
Organization:
University of Rochester
Study Overview
Official Title:
Understanding Coagulation and Inflammation in Burns
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to understand what happens to platelets and blood clotting factors in burn patients over time This study will also examine the role of microparticles MPs nanoparticles NPs and micro RNA in burns The investigators will be looking at small particles of cells that are released into the blood These particles have been found to be important in a variety of different diseases The investigators believe that MPs NPs and micro RNA may play a role in development of inflammation and infections in burn patients Thus hopefully this study will help understand how to minimize transfusions and bleeding in burn patients as well as how to reduce inflammation and infections in burn patients
Detailed Description:
Trauma injury is the leading cause of death in people 1-44 years old in the US Burn injury is a particularly debilitating form of trauma In the US the incidence of burn injury is estimated to be greater than 2 million cases per year Burns account for 300000 deaths worldwide every year In 1996 the cost of caring for burn patients in the US was estimated at 573 million per year
Notably 20-40 of trauma deaths that occur after hospital admission involve massive bleeding Hemorrhage is the second most common cause of early in-hospital mortality accounting for a large portion of trauma deaths that occur within the first 24 hours Resuscitation has dramatically changed over the last decade or so Nowadays we are substituting the normal saline and the other resuscitating fluids with blood products This early administration of blood products during resuscitation is referred to as damage control resuscitation DCR The goal of DCR is to prevent and immediately correct trauma associated coagulopathy DCR was initially practiced in the military where a balanced ratio of FFPplateletsRBCs of 111 was employed DCR has resulted in improved outcomes in both the military as well as civilian trauma setting as compared to previous resuscitation patterns Despite the early use of a 111 ratio a 112 ratio also became commonly used Thus the Pragmatic Randomized Optimal Platelet and Plasma Ratios PROPPR study was done to investigate the best ratio of products to use during resuscitation The PROPPR study found no differences in mortality between the 111 and the 112 groups at 24 hours or at 30 days Additionally there was no difference in complications between the two groups Notably exsanguination was significantly decreased in the 111 group and more patients in the 111 group reached hemostasis The Prospective Observational Multicenter Major Trauma Transfusion PROMMTT study showed that early transfusion within minutes of arriving at hospital was associated with improved 6-hour survival Furthermore patients with increased plasma to RBC ratios 12 were found to have improved 30-day survival as compared to patients who received lower plasma to RBC ratios 12 Notably 1-day and 30-day survival were found to be increased when patients received higher ratios of platelets to RBCs Delayed but balanced transfusion ratios did not have the same protective effect as receiving plasma early
To date there have been few studies on the effects of hemorrhage during burn and soft tissue excision and optimal blood product resuscitation It is unclear whether DCR is optimal in burn patients Moreover it is unknown exactly what is happening in burn patients with respect to coagulation platelet function and microparticles MPs Patients with burns and soft tissue injuries typically have considerable bleeding during surgeries Intraoperative blood loss is estimated at 92 of blood volume for every 1 of total body surface area TBSA burn excised in adults In children undergoing burn excision blood loss is estimated as 2 of blood volume for every 1 TBSA excised in extremities and trunk and 5 of blood volume for each 1 TBSA excised for the face Moreover early complete excision and grafting of major burns has been shown to decrease transfusions infections and mortality in children Interestingly many burn surgeons anecdotally report that their burn patients develop microvascular bleeding during the surgery This phenomenon may be indicative of development of coagulopathy
There have been several prospective studies looking at perioperative coagulation status in burn patients These studies show that the coagulation proteins FV FVIII FIX and fibrinogen decrease during surgery Notably in most cases the factor levels were still within normal reference ranges FVIII and fibrinogen are acute phase reactants and were elevated in the burn patients preoperatively These studies were performed before the adoption of DCR Additionally several studies have shown that antithrombin protein S and protein C the natural anticoagulants levels decrease in burn injuries A recent study by Palmieri et al looked at compared a transfusion ratio of 11 RBCsFFP to 41 RBCsFFP in children with 20 TBSA burns In their study of 16 children they found a trend toward increased length of stay LOS peak PELOD score measure of organ dysfunction increased time to wound healing and increased infection rates in the 41 group however the differences were not statistically significant Notably they found that the 1 1 ratio was safe in the burn patients and that the 11 ratio was also less expensive 26635 versus 34485 A recent study by Pidcoke et al showed that current blood product resuscitation during burn and soft tissue excision is not hemostatic Thus the effect of using a balanced resuscitation ratio of blood products including platelets in burn patients has not been well studied
In general platelet dysfunction is believed to play a role in the development of trauma associated coagulopathy TAC The effect of burns on patients platelets count and activity is unknown Upon hospital admission burn patients typically have normal platelet counts By days 3-5 the patients platelet counts usually drop especially in burns of large TBSA In severe burn patients platelet mediators such as platelet factor 4 PF4 and thromboxane B2 TxB2 have been found to be elevated This is thought to be attributable to platelet activation and consumption Thus further investigation of the effect of burns on platelets will offer further insight into the transfusion needs of burn patients
In a study done by Lu et al on the development of TAC in burn patients TAC was defined as an INR 13 aPTT 15 times the mean normal limit and normal platelet counts no patient presented with TAC upon admission Only few changes in INR and aPTT values were observed over time Further studies are needed however the authors may have underdiagnosed TAC in the burn patients based upon their definition of TAC It is likely that platelets and MPs play a significant role in the development of TAC as well as the bleeding seen in burn patients during excision and grafting
MPs are small vesicles 1 µm that resemble their parent cell in terms of similar surface proteins and membrane lipids Interestingly all blood cells can release MPs The most abundant MPs in the blood are platelet MPs PMPs PMPs have been found to have 50- to 100-fold higher procoagulant activity than activated whole platelets PMPs are formed via five mechanisms 1 platelet activation and subsequent shedding of membrane fragments 2 complement mediated membrane attack 3 high shear forces 4 senescence and apoptosis of platelets and megakaryocytes and 5 platelet cytoskeletal abnormalities In the PROMMTT study patient were found to have increased levels of MPs derived from endothelial cells RBCs and leukocytes as well as increased levels of tissue factor bearing MPs TF-MPs Notably coagulopathic trauma patients were found to have much lower levels of PMPs TF-MPs and thrombin generation in addition to more bleeding and increased mortality
To further understand the role of PMPs Matijevic et al examined PMPs in plasma They compared thawed plasma at day 5 to freshly thawed fresh frozen plasma FFP at day 0 They found that the majority of MPs were indeed PMPs and that day 5 plasma had a 50 reduction in MPs and a 29 decrease in procoagulant activity A recent prospective observational study of trauma patients found that patients with low levels of phosphatidylserine PS positive PMPs had impaired clot formation and were more likely to receive more RBC transfusions during the first 24 hours following injury These studies suggest that PMPs may play an important previously overlooked role in TAC The role of MPs in burn patients is unknown It is likely that MPs play a significant and overlooked role in the coagulation and development of coagulopathies in burn patients Further studies are needed to further evaluate the role of MPs particularly the number identity size and contribution to coagulation in burn patients
Following surgery with burn excision and grafting patients remain hospitalized for various lengths of time This often depends upon the TBSA burned smoke inhalation and infectious complications and other complicating medical problems Based upon previous studies burn patients are thought to become hypercoagulable This hypercoagulable state has been attributed to increased levels of some clotting factors FV FVIII platelets and fibrinogen and decreased levels of antithrombin protein S and protein C Notably the incidence of deep vein thrombosis DVT and pulmonary embolism PE in burn patients is low A study using the National Burn Repository database found the rate of venous thromboembolism VTE to be 061 Another study found the rate to be 025 for DVT and 005 for PE Yet another study which used duplex ultrasonography to screen burn patients for DVT on admission and at discharge found a prevalence of 61 Thus the rate of VTE in burn patients is thought to be much higher than previously expected due to asymptomatic DVTs as well as the difficulty in diagnosing DVTs in this population due to overlapping symptoms between DVTs and burns ex extremity swelling
There have been several published reports of VTE in burn patients Recently Van Haren et al studied the coagulation status of 24 burn patients over the course of their hospital stay using thromboelastography TEG and standard laboratory coagulation tests Notably repeat samples taken one week after admission were found to be hypercoagulable decreased R and K times increased α angle and increased MA and levels of fibrinogen protein S protein C and antithrombin were found to be increased Two patients that were hypercoagulable TEG showing decreased R time at admission were found to later develop VTE despite anticoagulation therapy Surprisingly prophylactic use of anticoagulation is not overall common in burn patients A survey of burn centers showed that about one quarter of USA centers did not use any form of VTE prophylaxis Thus additional studies are needed to further explore the coagulation status and various coagulation and anticoagulation factor levels of burn patients throughout their hospital course Only by understanding what is physiologically taking place in these patients can we offer the best therapeutic treatment no anticoagulation versus anticoagulation and if so which one
The goal of the proposed study is to further understand the physiologic changes that occur initially in burn patients and how the coagulation status of the burn patient changes over time In addition to changes in coagulation and anticoagulation proteins this study will focus on the effect of burns on platelets and MPs We will also examine the MP populations and characterize the identity size PS content of the MPs and elucidate their effect on coagulation parameters as well as inflammation
Notably 20-40 of trauma deaths that occur after hospital admission involve massive bleeding Hemorrhage is the second most common cause of early in-hospital mortality accounting for a large portion of trauma deaths that occur within the first 24 hours Resuscitation has dramatically changed over the last decade or so Nowadays we are substituting the normal saline and the other resuscitating fluids with blood products This early administration of blood products during resuscitation is referred to as damage control resuscitation DCR The goal of DCR is to prevent and immediately correct trauma associated coagulopathy DCR was initially practiced in the military where a balanced ratio of FFPplateletsRBCs of 111 was employed DCR has resulted in improved outcomes in both the military as well as civilian trauma setting as compared to previous resuscitation patterns Despite the early use of a 111 ratio a 112 ratio also became commonly used Thus the Pragmatic Randomized Optimal Platelet and Plasma Ratios PROPPR study was done to investigate the best ratio of products to use during resuscitation The PROPPR study found no differences in mortality between the 111 and the 112 groups at 24 hours or at 30 days Additionally there was no difference in complications between the two groups Notably exsanguination was significantly decreased in the 111 group and more patients in the 111 group reached hemostasis The Prospective Observational Multicenter Major Trauma Transfusion PROMMTT study showed that early transfusion within minutes of arriving at hospital was associated with improved 6-hour survival Furthermore patients with increased plasma to RBC ratios 12 were found to have improved 30-day survival as compared to patients who received lower plasma to RBC ratios 12 Notably 1-day and 30-day survival were found to be increased when patients received higher ratios of platelets to RBCs Delayed but balanced transfusion ratios did not have the same protective effect as receiving plasma early
To date there have been few studies on the effects of hemorrhage during burn and soft tissue excision and optimal blood product resuscitation It is unclear whether DCR is optimal in burn patients Moreover it is unknown exactly what is happening in burn patients with respect to coagulation platelet function and microparticles MPs Patients with burns and soft tissue injuries typically have considerable bleeding during surgeries Intraoperative blood loss is estimated at 92 of blood volume for every 1 of total body surface area TBSA burn excised in adults In children undergoing burn excision blood loss is estimated as 2 of blood volume for every 1 TBSA excised in extremities and trunk and 5 of blood volume for each 1 TBSA excised for the face Moreover early complete excision and grafting of major burns has been shown to decrease transfusions infections and mortality in children Interestingly many burn surgeons anecdotally report that their burn patients develop microvascular bleeding during the surgery This phenomenon may be indicative of development of coagulopathy
There have been several prospective studies looking at perioperative coagulation status in burn patients These studies show that the coagulation proteins FV FVIII FIX and fibrinogen decrease during surgery Notably in most cases the factor levels were still within normal reference ranges FVIII and fibrinogen are acute phase reactants and were elevated in the burn patients preoperatively These studies were performed before the adoption of DCR Additionally several studies have shown that antithrombin protein S and protein C the natural anticoagulants levels decrease in burn injuries A recent study by Palmieri et al looked at compared a transfusion ratio of 11 RBCsFFP to 41 RBCsFFP in children with 20 TBSA burns In their study of 16 children they found a trend toward increased length of stay LOS peak PELOD score measure of organ dysfunction increased time to wound healing and increased infection rates in the 41 group however the differences were not statistically significant Notably they found that the 1 1 ratio was safe in the burn patients and that the 11 ratio was also less expensive 26635 versus 34485 A recent study by Pidcoke et al showed that current blood product resuscitation during burn and soft tissue excision is not hemostatic Thus the effect of using a balanced resuscitation ratio of blood products including platelets in burn patients has not been well studied
In general platelet dysfunction is believed to play a role in the development of trauma associated coagulopathy TAC The effect of burns on patients platelets count and activity is unknown Upon hospital admission burn patients typically have normal platelet counts By days 3-5 the patients platelet counts usually drop especially in burns of large TBSA In severe burn patients platelet mediators such as platelet factor 4 PF4 and thromboxane B2 TxB2 have been found to be elevated This is thought to be attributable to platelet activation and consumption Thus further investigation of the effect of burns on platelets will offer further insight into the transfusion needs of burn patients
In a study done by Lu et al on the development of TAC in burn patients TAC was defined as an INR 13 aPTT 15 times the mean normal limit and normal platelet counts no patient presented with TAC upon admission Only few changes in INR and aPTT values were observed over time Further studies are needed however the authors may have underdiagnosed TAC in the burn patients based upon their definition of TAC It is likely that platelets and MPs play a significant role in the development of TAC as well as the bleeding seen in burn patients during excision and grafting
MPs are small vesicles 1 µm that resemble their parent cell in terms of similar surface proteins and membrane lipids Interestingly all blood cells can release MPs The most abundant MPs in the blood are platelet MPs PMPs PMPs have been found to have 50- to 100-fold higher procoagulant activity than activated whole platelets PMPs are formed via five mechanisms 1 platelet activation and subsequent shedding of membrane fragments 2 complement mediated membrane attack 3 high shear forces 4 senescence and apoptosis of platelets and megakaryocytes and 5 platelet cytoskeletal abnormalities In the PROMMTT study patient were found to have increased levels of MPs derived from endothelial cells RBCs and leukocytes as well as increased levels of tissue factor bearing MPs TF-MPs Notably coagulopathic trauma patients were found to have much lower levels of PMPs TF-MPs and thrombin generation in addition to more bleeding and increased mortality
To further understand the role of PMPs Matijevic et al examined PMPs in plasma They compared thawed plasma at day 5 to freshly thawed fresh frozen plasma FFP at day 0 They found that the majority of MPs were indeed PMPs and that day 5 plasma had a 50 reduction in MPs and a 29 decrease in procoagulant activity A recent prospective observational study of trauma patients found that patients with low levels of phosphatidylserine PS positive PMPs had impaired clot formation and were more likely to receive more RBC transfusions during the first 24 hours following injury These studies suggest that PMPs may play an important previously overlooked role in TAC The role of MPs in burn patients is unknown It is likely that MPs play a significant and overlooked role in the coagulation and development of coagulopathies in burn patients Further studies are needed to further evaluate the role of MPs particularly the number identity size and contribution to coagulation in burn patients
Following surgery with burn excision and grafting patients remain hospitalized for various lengths of time This often depends upon the TBSA burned smoke inhalation and infectious complications and other complicating medical problems Based upon previous studies burn patients are thought to become hypercoagulable This hypercoagulable state has been attributed to increased levels of some clotting factors FV FVIII platelets and fibrinogen and decreased levels of antithrombin protein S and protein C Notably the incidence of deep vein thrombosis DVT and pulmonary embolism PE in burn patients is low A study using the National Burn Repository database found the rate of venous thromboembolism VTE to be 061 Another study found the rate to be 025 for DVT and 005 for PE Yet another study which used duplex ultrasonography to screen burn patients for DVT on admission and at discharge found a prevalence of 61 Thus the rate of VTE in burn patients is thought to be much higher than previously expected due to asymptomatic DVTs as well as the difficulty in diagnosing DVTs in this population due to overlapping symptoms between DVTs and burns ex extremity swelling
There have been several published reports of VTE in burn patients Recently Van Haren et al studied the coagulation status of 24 burn patients over the course of their hospital stay using thromboelastography TEG and standard laboratory coagulation tests Notably repeat samples taken one week after admission were found to be hypercoagulable decreased R and K times increased α angle and increased MA and levels of fibrinogen protein S protein C and antithrombin were found to be increased Two patients that were hypercoagulable TEG showing decreased R time at admission were found to later develop VTE despite anticoagulation therapy Surprisingly prophylactic use of anticoagulation is not overall common in burn patients A survey of burn centers showed that about one quarter of USA centers did not use any form of VTE prophylaxis Thus additional studies are needed to further explore the coagulation status and various coagulation and anticoagulation factor levels of burn patients throughout their hospital course Only by understanding what is physiologically taking place in these patients can we offer the best therapeutic treatment no anticoagulation versus anticoagulation and if so which one
The goal of the proposed study is to further understand the physiologic changes that occur initially in burn patients and how the coagulation status of the burn patient changes over time In addition to changes in coagulation and anticoagulation proteins this study will focus on the effect of burns on platelets and MPs We will also examine the MP populations and characterize the identity size PS content of the MPs and elucidate their effect on coagulation parameters as well as inflammation
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None