Original article 33
Effects of recombinant activated factor VIIa on abdominal trauma patients Danhua Yao, Yousheng Li, Jian Wang, Wenkui Yu, Ning Li and Jieshou Li Recombinant activated factor VIIa (rFVIIa) has been highlighted by correcting uncontrollable traumatic haemorrhage. Compared with routine coagulation tests, thromboelastography (TEG) can evaluate the coagulation function of trauma patients more rapidly, accurately and comprehensively, and can also diagnose traumaassociated coagulopathy (TAC) in an early stage. Thirtyeight cases conforming to rFVIIa indications were screened according to TEG results and divided into an rFVIIa group (n U 20) and a nonrFVIIa group (n U 18). Their coagulopathy was goal-directedly corrected under the guidance of TEG. The parameters examined by routine coagulation tests and TEG were compared. The blood components transfused in the two groups were also calculated. When rFVIIa was administered by an average dose of 52.3 mg/kg (24.0– 95.6 mg/kg), blood coagulation function was significantly improved in 48 h. Compared with the nonrFVIIa group, the treatment group experienced decreased R time. Moreover, significant fewer red blood cells, platelet and fresh frozen plasma were transfused in the rFVIIa group. All patients underwent daily bedside vascular ultrasound screening
within a week after haemostatic treatment, of which no thromboembolic events occurred. TEG can sensitively detect TAC. rFVIIa administered goal-directedly guided by TEG is more effectively in correcting TAC and decreasing the amount of blood product transfusion. Blood Coagul Fibrinolysis 25:33–38 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:33–38 Keywords: recombinant activated factor VIIa, thromboelastography, trauma, trauma-associated coagulopathy Department of Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, P.R. China Correspondence to Yousheng Li, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China Tel: +86 013813001201; e-mail: [email protected] Received 24 July 2013 Revised 09 October 2013 Accepted 09 October 2013
Introduction
Patients and methods
Severe trauma, which leads to hypothermia, acidosis and coagulopathy, has been referred to as ‘bloody vicious cycle’ by Kashuk et al. [1]. Trauma patients are prone to dying of uncontrollable bleeding [2], which can be prevented by early diagnosis and treatment of coagulopathy. Compared with routine coagulation tests, thromboelastography (TEG) can evaluate the coagulation function of trauma patients more rapidly, accurately and comprehensively, and can also diagnose traumaassociated coagulopathy (TAC) in an early stage [3,4]. Moreover, TEG is adept at early detecting and treating TAC [5]. In recent years, goal-directed management of coagulopathy, which was proposed on the basis of the results of TEG, has succeeded in the haemostatic resuscitation of patients according to their specific conditions, thus reducing the mortality rate of TAC [2]. On the contrary, factor VIIa is a promoter of extrinsic coagulation pathway, and recombinant activated factor VIIa (rFVIIa) has been highlighted by correcting uncontrollable traumatic haemorrhage [6]. In this study, goal-directed therapy was performed on 38 TAC patients under the guidance of TEG. As a national emergency rescue centre for abdominal trauma, our hospital is dedicated to treating the haemorrhage of abdomen other than those of brain, chest, os pelvicum and limbs. Thus, the results herein are of great significance.
General information
0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
This study has been approved by the ethical committee of Jinling Hospital. Consent has been obtained before examination and treatment for enrolled patients according to the Declaration of Helsinki and relevant laws in China. All treatments were performed on the basis of the patients’ best interests. Ninety-one abdominal trauma patients treated in our hospital from June 2010 to June 2013 were retrospectively analysed. Thirty-eight patients in accordance with rFVIIa indications [TEG maximum amplitude (MA) 8 min? Yes
No
Is α < 60º?
FFP Yes
No
Is MA < 55mm?
CRYO after transfusing FFP Yes
PLT or rFVIIa
No
Recheck TEG
Algorithm of goal-directed management of coagulopathy guided by thromboelastography (TEG). CRYO, cryoprecipitate; FFP, fresh frozen plasma; MA, maximum amplitude; PLT, platelets.
TEG and routine coagulation indices, including prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (Fib), platelet, R, K, a angle and MA value, were observed and recorded before and on the second day after haemostatic treatments, respectively. All doses of rFVIIa are listed in Fig. 3 in detail. The component and volume of blood transfusion were calculated in the first 48 h since the beginning of haemostatic treatment. Blood samples for the routine detection and TEG originated from a same tube of blood within a single collection. Within 1 week after haemostatic products were given, vascular ultrasound examination was conducted on the lower and upper limbs of patients every day. Both groups were examined by vascular ultrasound, which was mostly conducted at the bedside to observe the incidence of thromboembolic events.
expressed as (mean standard deviation). For normally distributed variables, t-test was used to compare the coagulation indices between groups before and after haemostatic treatment. Categorical variables were Fig. 3
10
Survive Dead
8
Number of patients
Observation and examination indices
6
4
2
0
1 or 2 doses
3 or 4 doses
5 doses or more
Statistical analysis
All data were statistically analysed by SPSS 18.0 (SPSS Inc., Chicago, Illinois, USA). All coagulation indices were
Comparison of survival rates at different doses.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
36 Blood Coagulation and Fibrinolysis
2014, Vol 25 No 1
expressed as absolute numbers or in percentages, and were analysed with the chi-square test. P value less than 0.05 was considered as statistically significantly different.
Results One out of the 20 patients receiving rFVIIa treatment died complicated with multiple organ failures, and two died of uncontrollable haemorrhage. Of the 18 patients without rFVIIa treatment, two died of uncontrollable haemorrhage. The remaining 33 patients who survived for 1 week were subjected to further retrospective study. All patients in rFVIIa group were administered with 52.3 mg/kg rFVIIa in average (24.0–95.6 mg/kg) (Fig. 3). Thromboelastography and routine coagulation indices before and after haemostasis products treatments
In the rFVIIa group, Hb, PT, international normalized ratio (INR) and APTT after rFVIIa treatment were significantly different from those before (P < 0.05), but platelets (PLT) and Fib did not change significantly. The R and K values were significantly decreased, and a angle and MA value were significantly increased after rFVIIa treatment compared with those before (P < 0.05). After being treated with blood components, Hb, PLT, INR, R and K of the control group differed significantly from those before (P < 0.05), but PT, Fib, APTT, a and MA were similar. We used independent-sample t-test to assess the parameters of coagulation after haemostasis treatment between the two groups. A significantly shorter R time was found in the rFVIIa group and higher platelet counts were found in the non-rFVIIa group. Compared with the non-rFVIIa group, significant fewer RBP, platelet and FFP were transfused in the rFVIIa group. However, there were no differences in cryoprecipitate administration between the two groups. Incidence of thromboembolic events
All patients underwent daily bedside vascular ultrasound screening within a week after using haemostatic products, of which no thromboembolic events occurred.
Discussion Coagulopathy at the beginning of trauma was first referred to as acute traumatic coagulopathy (ATC) by Brohi et al. [7], which focuses on the event prior to medical intervention and fluid resuscitation. In this study, most patients had received treatments, such as haemostasis, abdominal packing, rewarming and antishock therapy, and so on, on the way to hospital or in emergency room. Some patients had received one or two surgeries in other hospitals. Therefore, the coagulopathy herein was essentially manifested as TAC resulting from the interaction between multiple mechanisms accompanied by a sophisticated pathogenesis. Actually, TAC may be induced by tissue injury, tissue hypoperfusion, haemodilution, hypothermia, acidosis and inflammatory response [8].
Traditionally, PT, APTT, TT, Fib, PLT and other coagulation indices are examined laboratorily, which, however, cannot reflect the real-time changes of coagulation. In contrast, bedside TEG works within half an hour, thus allowing clinicians to diagnose timely. Previous studies have shown that TEG outweighed routine coagulation tests in the diagnosis of coagulation due to trauma [5,9]. In this study, PT, Fib and APTT were not significantly altered after haemostatic treatment in the non-rFVIIa group, but TEG detected significantly changed R, K and MA. Hence, TEG reveals the changes of coagulation better than routine coagulation tests do. Factor VIIa, a promoter of extrinsic coagulation pathway, forms a factor VIIa–tissue factor complex and activates factors IX and X by directly binding tissue factor after being activated [10], thereby facilitating coagulation by transforming prothrombin into thrombin. Meanwhile, VIIa also promotes coagulation by activating factor X after directly binding activated platelets. Moreover, VIIa merely promotes the haemostasis in local injured tissues without giving rise to systemic diffusive thrombosis. rFVIIa, which was initially used in treating haemophilia patients with antibodies of specific procoagulant factors VII and IX, has been gradually applied to treat TAC recently. In 2008, the meta-analysis of von Heymann et al. [11] showed that 73% of the patients receiving abdominal, vascular or urinary surgeries experienced a blood transfusion reduction after rFVIIa treatment, and more patients sensitive to rFVIIa treatment survived. Compared with the placebo group, rFVIIa did not increase the risk of thromboembolism. Moreover, a randomized clinical test named CONTROL [12] revealed that rFVIIa significantly lowered the transfusion amount of blood products without augmenting the incidence of thrombosis, or reducing the mortality rate of trauma patients compared with those of the placebo group. Regardless, some researchers held that rFVIIa should be used cautiously due to its potential risk of thrombosis [13]. The meta-analysis of Levi et al. [14] showed that the incidence rates of thromboembolism in surgical and trauma patients ranged between 1 and 2% after rFVIIa treatment, and the incidence of thromboembolism was positively correlated with the dose of rFVIIa [15]. Particularly, it is imperative to subject the patients with massive haemorrhage threatening life to further clinical trials regarding the influences of rFVIIa. The optimum doses of rFVIIa recommended in previous literatures ranged from 20 to 100 mg/kg [15,16]. Gill et al. [17] conducted a randomized placebo-controlled trial to assess the safety and efficacy of rFVIIa in the setting of bleeding after cardiac surgery. They randomized patients who had undergone cardiac surgeries and were bleeding to receive placebo, 40 mg/kg rFVIIa or 80 mg/kg rFVIIa.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
rFVIIa in abdominal trauma patients Yao et al. 37
Table 2
Parameters of coagulation before and after blood product and rFVIIa transfusion rFVIIa group (n ¼ 17)
Hb (g/l) PLT (109/l) PT (s) Fib (mg/dl) INR APTT (s) R (min) K (min) a (8) MA (mm)
Non-rFVIIa group (n ¼ 16)
Before
After
P
Before
After
P
71.1 12.7 92.5 67.2 18.1 7.7 253.5 113.6 1.58 0.66 55.0 27.8 23.0 15.9 13.3 8.2 28.9 17.0 41.3 11.2
84.9 6.4 92.4 44.4a 14.0 1.6 269.2 151.3 1.21 0.13 39.5 10.8 9.2 3.3a 7.3 5.4 44.8 14.4 52.5 9.4
0.002 0.992 0.049 0.620 0.042 0.013 0.002 0.013 0.004 0.003
70.6 12.5 89.3 50.4 17.9 7.9 246.0 115.5 1.57 0.35 50.2 26.0 22.7 8.8 12.9 6.8 27.6 12.2 43.7 7.1
82.7 5.5 150.3 61.2a 14.3 1.9 224.8 106.3 1.33 0.21 39.4 10.2 15.1 6.0a 9.0 4.8 34.1 17.2 49.1 10.3
0.001 0.008 0.116 0.549 0.011 0.050 0.004 0.010 0.128 0.078
APTT, activated partial thromboplastin time; Fib, fibrinogen; Hb, haemoglobin; INR, international normalized ratio; MA, maximum amplitude; PLT, platelet; PT, prothrombin time. a Means statistical difference was founded in R time and platelet counts between rFVIIa and non-rFVIIa groups after blood product and/or rFVIIa was administered (P < 0.05).
Thus, significantly fewer patients in the rFVIIa group received reoperations as a result of bleeding or required allogeneic transfusions. In this study, the average dose of rFVIIa was 52.3 mg/kg, and the minimum dose was 24.0 mg/kg. After rFVIIa treatment, TEG indices were improved compared with those before, verifying that low-dose rFVIIa could also correct TAC. More patients died after being treated with over five doses of rFVIIa without dying of thromboembolism probably because the high-dose group suffered more severely. The goal-directed coagulation management in this study was formulated referring to the resuscitation method for trauma patients under the guidance of r-TEG by Denver Health and Medical Center [18], based on sufficient experiences in treating trauma patients in our hospital [19]. However, as to the trauma patients mainly manifested as abdominal closed injury, their visceral organs are susceptible to latent or tardive haemorrhage owing to multiple injury factors. Although rFVIIa can effectively correct coagulopathy, it can neither substitute surgical definitive haemostasis and exploration, nor postpone surgeries. In some cases, when TEG showed MA was lower than 55 mm, both rFVIIa and platelet were infused even if platelet count was not lower than 50 109/l. Therefore, we had to exclude these patients out of this retrospective study. In some patients, TEG was repeated multiple
times. The last TEG examined before administration of haemostatic products was selected as ‘before treatment’ in Table 2, and the last TEG examined after the last dose of rFVIIa was infused on the second day and was selected as ‘after treatment’. MA was significantly increased in the rFVIIa group, but was still less than normal. Even though much more platelet was infused and higher platelet counts were detected in the non-rFVIIa group, MA did not differ significantly before and after haemostatic treatment. Probably, coagulopathy could not be corrected by simply increasing the count of platelet, but by improving the function of platelet. rFVIIa was a good promoter of coagulation that reduced R time and increased MA. Meanwhile, it could also reduce the amounts of RBC, FFP and PLT in resuscitation (Table 3). This retrospective study is limited in the small sample size, and the observation did not last long enough. Meanwhile, bedside vascular ultrasound was used herein to screen thrombosis due to the limitations of patient conditions, which may have neglected some latent thrombosis in brain, lung, portal vein, mesenteric vein and so on. Maybe this study was underpowered to detect the incidence of thromboembolism. Further studies are still ongoing in our group.
Acknowledgements This work is financially supported by the 12th Five Years Programs for Science and Technology Major Project of Chinese People’s Liberation Army (AWS12J001).
Volume of blood products transfused in the two groups during 48 h
Table 3
RBC (U) FFP (U) CRYO (U) PLT (U)
rFVIIa group (n ¼ 17)
Non-rFVIIa group (n ¼ 16)
P
11.6 3.1 10.1 2.0 16.8 9.4 1.8 3.9
14.8 4.6 12.0 2.7 20.2 7.5 16.9 7.9
0.029 0.033 0.263
Effects of recombinant activated factor VIIa on abdominal trauma patients Danhua Yao, Yousheng Li, Jian Wang, Wenkui Yu, Ning Li and Jieshou Li Recombinant activated factor VIIa (rFVIIa) has been highlighted by correcting uncontrollable traumatic haemorrhage. Compared with routine coagulation tests, thromboelastography (TEG) can evaluate the coagulation function of trauma patients more rapidly, accurately and comprehensively, and can also diagnose traumaassociated coagulopathy (TAC) in an early stage. Thirtyeight cases conforming to rFVIIa indications were screened according to TEG results and divided into an rFVIIa group (n U 20) and a nonrFVIIa group (n U 18). Their coagulopathy was goal-directedly corrected under the guidance of TEG. The parameters examined by routine coagulation tests and TEG were compared. The blood components transfused in the two groups were also calculated. When rFVIIa was administered by an average dose of 52.3 mg/kg (24.0– 95.6 mg/kg), blood coagulation function was significantly improved in 48 h. Compared with the nonrFVIIa group, the treatment group experienced decreased R time. Moreover, significant fewer red blood cells, platelet and fresh frozen plasma were transfused in the rFVIIa group. All patients underwent daily bedside vascular ultrasound screening
within a week after haemostatic treatment, of which no thromboembolic events occurred. TEG can sensitively detect TAC. rFVIIa administered goal-directedly guided by TEG is more effectively in correcting TAC and decreasing the amount of blood product transfusion. Blood Coagul Fibrinolysis 25:33–38 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:33–38 Keywords: recombinant activated factor VIIa, thromboelastography, trauma, trauma-associated coagulopathy Department of Surgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, P.R. China Correspondence to Yousheng Li, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China Tel: +86 013813001201; e-mail: [email protected] Received 24 July 2013 Revised 09 October 2013 Accepted 09 October 2013
Introduction
Patients and methods
Severe trauma, which leads to hypothermia, acidosis and coagulopathy, has been referred to as ‘bloody vicious cycle’ by Kashuk et al. [1]. Trauma patients are prone to dying of uncontrollable bleeding [2], which can be prevented by early diagnosis and treatment of coagulopathy. Compared with routine coagulation tests, thromboelastography (TEG) can evaluate the coagulation function of trauma patients more rapidly, accurately and comprehensively, and can also diagnose traumaassociated coagulopathy (TAC) in an early stage [3,4]. Moreover, TEG is adept at early detecting and treating TAC [5]. In recent years, goal-directed management of coagulopathy, which was proposed on the basis of the results of TEG, has succeeded in the haemostatic resuscitation of patients according to their specific conditions, thus reducing the mortality rate of TAC [2]. On the contrary, factor VIIa is a promoter of extrinsic coagulation pathway, and recombinant activated factor VIIa (rFVIIa) has been highlighted by correcting uncontrollable traumatic haemorrhage [6]. In this study, goal-directed therapy was performed on 38 TAC patients under the guidance of TEG. As a national emergency rescue centre for abdominal trauma, our hospital is dedicated to treating the haemorrhage of abdomen other than those of brain, chest, os pelvicum and limbs. Thus, the results herein are of great significance.
General information
0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
This study has been approved by the ethical committee of Jinling Hospital. Consent has been obtained before examination and treatment for enrolled patients according to the Declaration of Helsinki and relevant laws in China. All treatments were performed on the basis of the patients’ best interests. Ninety-one abdominal trauma patients treated in our hospital from June 2010 to June 2013 were retrospectively analysed. Thirty-eight patients in accordance with rFVIIa indications [TEG maximum amplitude (MA) 8 min? Yes
No
Is α < 60º?
FFP Yes
No
Is MA < 55mm?
CRYO after transfusing FFP Yes
PLT or rFVIIa
No
Recheck TEG
Algorithm of goal-directed management of coagulopathy guided by thromboelastography (TEG). CRYO, cryoprecipitate; FFP, fresh frozen plasma; MA, maximum amplitude; PLT, platelets.
TEG and routine coagulation indices, including prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), fibrinogen (Fib), platelet, R, K, a angle and MA value, were observed and recorded before and on the second day after haemostatic treatments, respectively. All doses of rFVIIa are listed in Fig. 3 in detail. The component and volume of blood transfusion were calculated in the first 48 h since the beginning of haemostatic treatment. Blood samples for the routine detection and TEG originated from a same tube of blood within a single collection. Within 1 week after haemostatic products were given, vascular ultrasound examination was conducted on the lower and upper limbs of patients every day. Both groups were examined by vascular ultrasound, which was mostly conducted at the bedside to observe the incidence of thromboembolic events.
expressed as (mean standard deviation). For normally distributed variables, t-test was used to compare the coagulation indices between groups before and after haemostatic treatment. Categorical variables were Fig. 3
10
Survive Dead
8
Number of patients
Observation and examination indices
6
4
2
0
1 or 2 doses
3 or 4 doses
5 doses or more
Statistical analysis
All data were statistically analysed by SPSS 18.0 (SPSS Inc., Chicago, Illinois, USA). All coagulation indices were
Comparison of survival rates at different doses.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
36 Blood Coagulation and Fibrinolysis
2014, Vol 25 No 1
expressed as absolute numbers or in percentages, and were analysed with the chi-square test. P value less than 0.05 was considered as statistically significantly different.
Results One out of the 20 patients receiving rFVIIa treatment died complicated with multiple organ failures, and two died of uncontrollable haemorrhage. Of the 18 patients without rFVIIa treatment, two died of uncontrollable haemorrhage. The remaining 33 patients who survived for 1 week were subjected to further retrospective study. All patients in rFVIIa group were administered with 52.3 mg/kg rFVIIa in average (24.0–95.6 mg/kg) (Fig. 3). Thromboelastography and routine coagulation indices before and after haemostasis products treatments
In the rFVIIa group, Hb, PT, international normalized ratio (INR) and APTT after rFVIIa treatment were significantly different from those before (P < 0.05), but platelets (PLT) and Fib did not change significantly. The R and K values were significantly decreased, and a angle and MA value were significantly increased after rFVIIa treatment compared with those before (P < 0.05). After being treated with blood components, Hb, PLT, INR, R and K of the control group differed significantly from those before (P < 0.05), but PT, Fib, APTT, a and MA were similar. We used independent-sample t-test to assess the parameters of coagulation after haemostasis treatment between the two groups. A significantly shorter R time was found in the rFVIIa group and higher platelet counts were found in the non-rFVIIa group. Compared with the non-rFVIIa group, significant fewer RBP, platelet and FFP were transfused in the rFVIIa group. However, there were no differences in cryoprecipitate administration between the two groups. Incidence of thromboembolic events
All patients underwent daily bedside vascular ultrasound screening within a week after using haemostatic products, of which no thromboembolic events occurred.
Discussion Coagulopathy at the beginning of trauma was first referred to as acute traumatic coagulopathy (ATC) by Brohi et al. [7], which focuses on the event prior to medical intervention and fluid resuscitation. In this study, most patients had received treatments, such as haemostasis, abdominal packing, rewarming and antishock therapy, and so on, on the way to hospital or in emergency room. Some patients had received one or two surgeries in other hospitals. Therefore, the coagulopathy herein was essentially manifested as TAC resulting from the interaction between multiple mechanisms accompanied by a sophisticated pathogenesis. Actually, TAC may be induced by tissue injury, tissue hypoperfusion, haemodilution, hypothermia, acidosis and inflammatory response [8].
Traditionally, PT, APTT, TT, Fib, PLT and other coagulation indices are examined laboratorily, which, however, cannot reflect the real-time changes of coagulation. In contrast, bedside TEG works within half an hour, thus allowing clinicians to diagnose timely. Previous studies have shown that TEG outweighed routine coagulation tests in the diagnosis of coagulation due to trauma [5,9]. In this study, PT, Fib and APTT were not significantly altered after haemostatic treatment in the non-rFVIIa group, but TEG detected significantly changed R, K and MA. Hence, TEG reveals the changes of coagulation better than routine coagulation tests do. Factor VIIa, a promoter of extrinsic coagulation pathway, forms a factor VIIa–tissue factor complex and activates factors IX and X by directly binding tissue factor after being activated [10], thereby facilitating coagulation by transforming prothrombin into thrombin. Meanwhile, VIIa also promotes coagulation by activating factor X after directly binding activated platelets. Moreover, VIIa merely promotes the haemostasis in local injured tissues without giving rise to systemic diffusive thrombosis. rFVIIa, which was initially used in treating haemophilia patients with antibodies of specific procoagulant factors VII and IX, has been gradually applied to treat TAC recently. In 2008, the meta-analysis of von Heymann et al. [11] showed that 73% of the patients receiving abdominal, vascular or urinary surgeries experienced a blood transfusion reduction after rFVIIa treatment, and more patients sensitive to rFVIIa treatment survived. Compared with the placebo group, rFVIIa did not increase the risk of thromboembolism. Moreover, a randomized clinical test named CONTROL [12] revealed that rFVIIa significantly lowered the transfusion amount of blood products without augmenting the incidence of thrombosis, or reducing the mortality rate of trauma patients compared with those of the placebo group. Regardless, some researchers held that rFVIIa should be used cautiously due to its potential risk of thrombosis [13]. The meta-analysis of Levi et al. [14] showed that the incidence rates of thromboembolism in surgical and trauma patients ranged between 1 and 2% after rFVIIa treatment, and the incidence of thromboembolism was positively correlated with the dose of rFVIIa [15]. Particularly, it is imperative to subject the patients with massive haemorrhage threatening life to further clinical trials regarding the influences of rFVIIa. The optimum doses of rFVIIa recommended in previous literatures ranged from 20 to 100 mg/kg [15,16]. Gill et al. [17] conducted a randomized placebo-controlled trial to assess the safety and efficacy of rFVIIa in the setting of bleeding after cardiac surgery. They randomized patients who had undergone cardiac surgeries and were bleeding to receive placebo, 40 mg/kg rFVIIa or 80 mg/kg rFVIIa.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
rFVIIa in abdominal trauma patients Yao et al. 37
Table 2
Parameters of coagulation before and after blood product and rFVIIa transfusion rFVIIa group (n ¼ 17)
Hb (g/l) PLT (109/l) PT (s) Fib (mg/dl) INR APTT (s) R (min) K (min) a (8) MA (mm)
Non-rFVIIa group (n ¼ 16)
Before
After
P
Before
After
P
71.1 12.7 92.5 67.2 18.1 7.7 253.5 113.6 1.58 0.66 55.0 27.8 23.0 15.9 13.3 8.2 28.9 17.0 41.3 11.2
84.9 6.4 92.4 44.4a 14.0 1.6 269.2 151.3 1.21 0.13 39.5 10.8 9.2 3.3a 7.3 5.4 44.8 14.4 52.5 9.4
0.002 0.992 0.049 0.620 0.042 0.013 0.002 0.013 0.004 0.003
70.6 12.5 89.3 50.4 17.9 7.9 246.0 115.5 1.57 0.35 50.2 26.0 22.7 8.8 12.9 6.8 27.6 12.2 43.7 7.1
82.7 5.5 150.3 61.2a 14.3 1.9 224.8 106.3 1.33 0.21 39.4 10.2 15.1 6.0a 9.0 4.8 34.1 17.2 49.1 10.3
0.001 0.008 0.116 0.549 0.011 0.050 0.004 0.010 0.128 0.078
APTT, activated partial thromboplastin time; Fib, fibrinogen; Hb, haemoglobin; INR, international normalized ratio; MA, maximum amplitude; PLT, platelet; PT, prothrombin time. a Means statistical difference was founded in R time and platelet counts between rFVIIa and non-rFVIIa groups after blood product and/or rFVIIa was administered (P < 0.05).
Thus, significantly fewer patients in the rFVIIa group received reoperations as a result of bleeding or required allogeneic transfusions. In this study, the average dose of rFVIIa was 52.3 mg/kg, and the minimum dose was 24.0 mg/kg. After rFVIIa treatment, TEG indices were improved compared with those before, verifying that low-dose rFVIIa could also correct TAC. More patients died after being treated with over five doses of rFVIIa without dying of thromboembolism probably because the high-dose group suffered more severely. The goal-directed coagulation management in this study was formulated referring to the resuscitation method for trauma patients under the guidance of r-TEG by Denver Health and Medical Center [18], based on sufficient experiences in treating trauma patients in our hospital [19]. However, as to the trauma patients mainly manifested as abdominal closed injury, their visceral organs are susceptible to latent or tardive haemorrhage owing to multiple injury factors. Although rFVIIa can effectively correct coagulopathy, it can neither substitute surgical definitive haemostasis and exploration, nor postpone surgeries. In some cases, when TEG showed MA was lower than 55 mm, both rFVIIa and platelet were infused even if platelet count was not lower than 50 109/l. Therefore, we had to exclude these patients out of this retrospective study. In some patients, TEG was repeated multiple
times. The last TEG examined before administration of haemostatic products was selected as ‘before treatment’ in Table 2, and the last TEG examined after the last dose of rFVIIa was infused on the second day and was selected as ‘after treatment’. MA was significantly increased in the rFVIIa group, but was still less than normal. Even though much more platelet was infused and higher platelet counts were detected in the non-rFVIIa group, MA did not differ significantly before and after haemostatic treatment. Probably, coagulopathy could not be corrected by simply increasing the count of platelet, but by improving the function of platelet. rFVIIa was a good promoter of coagulation that reduced R time and increased MA. Meanwhile, it could also reduce the amounts of RBC, FFP and PLT in resuscitation (Table 3). This retrospective study is limited in the small sample size, and the observation did not last long enough. Meanwhile, bedside vascular ultrasound was used herein to screen thrombosis due to the limitations of patient conditions, which may have neglected some latent thrombosis in brain, lung, portal vein, mesenteric vein and so on. Maybe this study was underpowered to detect the incidence of thromboembolism. Further studies are still ongoing in our group.
Acknowledgements This work is financially supported by the 12th Five Years Programs for Science and Technology Major Project of Chinese People’s Liberation Army (AWS12J001).
Volume of blood products transfused in the two groups during 48 h
Table 3
RBC (U) FFP (U) CRYO (U) PLT (U)
rFVIIa group (n ¼ 17)
Non-rFVIIa group (n ¼ 16)
P
11.6 3.1 10.1 2.0 16.8 9.4 1.8 3.9
14.8 4.6 12.0 2.7 20.2 7.5 16.9 7.9
0.029 0.033 0.263
