Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study
ECMO patients exhibit a range of coagulation abnormalities including: consumption of both procoagulant and anticoagulant factors10,11, thrombocytopenia, altered vWF multimers12, platelet dysfunction1, decreased anti-thrombin2, as well as increased D-dimer, prothrombin fragment 1.2 and thrombin-antithrombin complexes13. Despite patients who require VA and VV ECMO support having substantially different characteristics and underlying pathologies, data on differences in underlying coagulation profiles is extremely limited and patients are often treated with the same anticoagulation protocols. Herein, using multiple measures of coagulation, we report the largest and most detailed study to date on the coagulation profiles in VA and VV ECMO patients, and confirm substantial differences between VA and VV coagulation profiles suggesting that coagulation management should be considered different between the two modalities.
A pattern of consumptive coagulopathy was present in VA patients; characterised by elevated d-dimers, bilirubin and lactate and prolonged prothrombin time and lower fibrinogen and platelet levels, decreased clot strength and platelet dysfunction. Further, VA patients received lower doses of heparin than VV patients to achieve similar aPTT levels, and had longer CK-R time but shorter CKH-R times by thromboelastography. These findings indicate that VA ECMO patients have higher consumption of clotting factors than VV patients, and that aPTT is a less reliable monitor of heparin therapy than in this group.
The differences in coagulation profile between VA and VV patients is likely in large part, to be explained by the differing baseline patient characteristics and underlying pathologies requiring support. VA patients with inherent cardiac dysfunction and periods of poor end-organ perfusion and liver dysfunction prior to, and during implementation of extracorporeal support may exhibit decreased coagulation factor production14. Moreover, 10 of our 19 VA patients received ECPR for cardiac arrest. Cardiac arrest results in systemic inflammation, increased coagulation factor consumption, disseminated intravascular coagulation (DIC), induction of tissue factor-dependent coagulation, impaired anticoagulant mechanisms15,16 and increased fibrinolysis16. Whilst the large proportion of ECPR patients in the VA group may contributed to some of differences when compared to VV patients, comparing non-ECPR VA patients to VV patients on subgroup analysis, differences in key parameters remained, thus supporting underlying differences between VA and VV patients independent of cardiac arrest status. Whilst cardiogenic shock with organ failure and a consumptive process appears to predominate in VA patients, ARDS patients typically exhibit an extreme inflammatory response with diffuse fibrin deposition17, a pro-coagulant response18 and massive thrombin generation17—differing underlying pathological processes.
Interestingly, significant differences were also seen between ECPR and non-ECPR patients in fibrinogen levels and lactate levels. This may be due to a more pronounced acute coagulative response in arrest patients.
We found lower indices of clot strength in with VA patients compared to VV patients with lower TEG Maximum Amplitude (MA); and lower G-value (a marker of overall platelet and fibrin performance). Low clot strength is predictive of bleeding events19 and a TEG CK G value below < 5 dynes/cm2 (as found in in our VA patients) is associated with increased risk of hemorrhage20. Our testing could not determine the relative contribution of hypofibrinogenemia, anti-platelet medication, intrinsic platelet dysfunction, and abnormal vWF on the abnormal clot strength.
Whilst hypofibrinogenemia and transient reduction in fibrinogen levels21 have been reported, many studies report normal or supranormal fibrinogen levels during ECMO19,21,22 (as we report in our VV patients) with an acute phase reaction from systemic inflammation in ARDS patients a likely contributor16. The decreased clot strength we found in our VA patients may have been caused by hypofibrinogenemia due to increased consumption and was most pronounced in ECPR patients presumably due to increased consumptive or fibrinolytic processes16.
We assessed platelet function with TEG Platelet Mapping and Multiplate Aggregometry and found that VA ECMO patients had significantly lower ADP activity and a trend to lower activity on TRAPtest results. ECMO related platelet dysfunction assessed by Multiplate aggregometry has been described previously in VV and VA ECMO patients23,24,25. Proposed mechanisms for this include: depletion of the stored platelet ADP26, sheer flow induced shedding of platelet adhesion glycoproteins27, loss of high molecular weight VWF multimers (HMWM) with reduced vWF activity28,29,30 and lower levels of platelet aggregation27,28,31,32. However, thrombocytopenia influences platelet function testing and some studies24,25 have not corrected for this. Balle et al. found no dysfunction compared to controls when results were corrected for platelet levels33. Thrombocytopenia, seen in our study, is common in both ECMO modalities34,35,36. Pre-ECMO platelet levels and development of critical illness may contribute to the its development37 more than duration of ECMO support and this may explain our finding of lower platelet count in VA compared to VV patients.
Relative thrombin generation in ECMO patients is only just being elucidated. Only one previous study of thrombin generation in VA patients has been reported38. Our study, is the first to look at residual thrombin generation in the presence of heparin effect during standard care in ECMO patients and demonstrates differences between VA and VV cohorts in response to UFH. Despite the expected large thrombin generation seen in ARDS patients on VV, our data suggested that VV patients were more likely to achieve thrombin suppression with lower anti-FXa levels than VA. The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation40. Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.
In heparinised patients demonstrating residual thrombin generation activity, anti-FXa levels, but not APTT, correlated with classical markers of thrombin generation indicating that anti-FXa may offer a more accurate method of guiding heparin dose, highlighted by the high variability in APTT at similar thrombin generation levels seen in the VA patients. In combination with our data showing the poor correlation between total heparin dose and aPTT, these results add to the literature suggesting that a randomised comparison between anti-FXa and aPTT as methods for adjusting UFH dosing in ECMO may be warranted. Clinical adjustments to monitoring UFH and changes to target ranges may also need to take in account inherent differences in VV versus VA patients in relationships between anti-FXa, aPTT levels and residual thrombin generation.
In our study only about one half of aPTT values were within prescribed range. This number is lower than documented in previous prospective randomised studies41 but higher than other cohort studies42 and reflects the difficulty in accurately titrating heparin in ECMO patients. VA patients had a higher proportion of aPTTs above the therapeutic range despite lower total heparin dosage and anti-FXa levels. A
ECMO patients exhibit a range of coagulation abnormalities including: consumption of both procoagulant and anticoagulant factors10,11, thrombocytopenia, altered vWF multimers12, platelet dysfunction1, decreased anti-thrombin2, as well as increased D-dimer, prothrombin fragment 1.2 and thrombin-antithrombin complexes13. Despite patients who require VA and VV ECMO support having substantially different characteristics and underlying pathologies, data on differences in underlying coagulation profiles is extremely limited and patients are often treated with the same anticoagulation protocols. Herein, using multiple measures of coagulation, we report the largest and most detailed study to date on the coagulation profiles in VA and VV ECMO patients, and confirm substantial differences between VA and VV coagulation profiles suggesting that coagulation management should be considered different between the two modalities.
A pattern of consumptive coagulopathy was present in VA patients; characterised by elevated d-dimers, bilirubin and lactate and prolonged prothrombin time and lower fibrinogen and platelet levels, decreased clot strength and platelet dysfunction. Further, VA patients received lower doses of heparin than VV patients to achieve similar aPTT levels, and had longer CK-R time but shorter CKH-R times by thromboelastography. These findings indicate that VA ECMO patients have higher consumption of clotting factors than VV patients, and that aPTT is a less reliable monitor of heparin therapy than in this group.
The differences in coagulation profile between VA and VV patients is likely in large part, to be explained by the differing baseline patient characteristics and underlying pathologies requiring support. VA patients with inherent cardiac dysfunction and periods of poor end-organ perfusion and liver dysfunction prior to, and during implementation of extracorporeal support may exhibit decreased coagulation factor production14. Moreover, 10 of our 19 VA patients received ECPR for cardiac arrest. Cardiac arrest results in systemic inflammation, increased coagulation factor consumption, disseminated intravascular coagulation (DIC), induction of tissue factor-dependent coagulation, impaired anticoagulant mechanisms15,16 and increased fibrinolysis16. Whilst the large proportion of ECPR patients in the VA group may contributed to some of differences when compared to VV patients, comparing non-ECPR VA patients to VV patients on subgroup analysis, differences in key parameters remained, thus supporting underlying differences between VA and VV patients independent of cardiac arrest status. Whilst cardiogenic shock with organ failure and a consumptive process appears to predominate in VA patients, ARDS patients typically exhibit an extreme inflammatory response with diffuse fibrin deposition17, a pro-coagulant response18 and massive thrombin generation17—differing underlying pathological processes.
Interestingly, significant differences were also seen between ECPR and non-ECPR patients in fibrinogen levels and lactate levels. This may be due to a more pronounced acute coagulative response in arrest patients.
We found lower indices of clot strength in with VA patients compared to VV patients with lower TEG Maximum Amplitude (MA); and lower G-value (a marker of overall platelet and fibrin performance). Low clot strength is predictive of bleeding events19 and a TEG CK G value below < 5 dynes/cm2 (as found in in our VA patients) is associated with increased risk of hemorrhage20. Our testing could not determine the relative contribution of hypofibrinogenemia, anti-platelet medication, intrinsic platelet dysfunction, and abnormal vWF on the abnormal clot strength.
Whilst hypofibrinogenemia and transient reduction in fibrinogen levels21 have been reported, many studies report normal or supranormal fibrinogen levels during ECMO19,21,22 (as we report in our VV patients) with an acute phase reaction from systemic inflammation in ARDS patients a likely contributor16. The decreased clot strength we found in our VA patients may have been caused by hypofibrinogenemia due to increased consumption and was most pronounced in ECPR patients presumably due to increased consumptive or fibrinolytic processes16.
We assessed platelet function with TEG Platelet Mapping and Multiplate Aggregometry and found that VA ECMO patients had significantly lower ADP activity and a trend to lower activity on TRAPtest results. ECMO related platelet dysfunction assessed by Multiplate aggregometry has been described previously in VV and VA ECMO patients23,24,25. Proposed mechanisms for this include: depletion of the stored platelet ADP26, sheer flow induced shedding of platelet adhesion glycoproteins27, loss of high molecular weight VWF multimers (HMWM) with reduced vWF activity28,29,30 and lower levels of platelet aggregation27,28,31,32. However, thrombocytopenia influences platelet function testing and some studies24,25 have not corrected for this. Balle et al. found no dysfunction compared to controls when results were corrected for platelet levels33. Thrombocytopenia, seen in our study, is common in both ECMO modalities34,35,36. Pre-ECMO platelet levels and development of critical illness may contribute to the its development37 more than duration of ECMO support and this may explain our finding of lower platelet count in VA compared to VV patients.
Relative thrombin generation in ECMO patients is only just being elucidated. Only one previous study of thrombin generation in VA patients has been reported38. Our study, is the first to look at residual thrombin generation in the presence of heparin effect during standard care in ECMO patients and demonstrates differences between VA and VV cohorts in response to UFH. Despite the expected large thrombin generation seen in ARDS patients on VV, our data suggested that VV patients were more likely to achieve thrombin suppression with lower anti-FXa levels than VA. The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation40. Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.
In heparinised patients demonstrating residual thrombin generation activity, anti-FXa levels, but not APTT, correlated with classical markers of thrombin generation indicating that anti-FXa may offer a more accurate method of guiding heparin dose, highlighted by the high variability in APTT at similar thrombin generation levels seen in the VA patients. In combination with our data showing the poor correlation between total heparin dose and aPTT, these results add to the literature suggesting that a randomised comparison between anti-FXa and aPTT as methods for adjusting UFH dosing in ECMO may be warranted. Clinical adjustments to monitoring UFH and changes to target ranges may also need to take in account inherent differences in VV versus VA patients in relationships between anti-FXa, aPTT levels and residual thrombin generation.
In our study only about one half of aPTT values were within prescribed range. This number is lower than documented in previous prospective randomised studies41 but higher than other cohort studies42 and reflects the difficulty in accurately titrating heparin in ECMO patients. VA patients had a higher proportion of aPTTs above the therapeutic range despite lower total heparin dosage and anti-FXa levels. A ma
ECMO patients exhibit a range of coagulation abnormalities including: consumption of both procoagulant and anticoagulant factors10,11, thrombocytopenia, altered vWF multimers12, platelet dysfunction1, decreased anti-thrombin2, as well as increased D-dimer, prothrombin fragment 1.2 and thrombin-antithrombin complexes13. Despite patients who require VA and VV ECMO support having substantially different characteristics and underlying pathologies, data on differences in underlying coagulation profiles is extremely limited and patients are often treated with the same anticoagulation protocols. Herein, using multiple measures of coagulation, we report the largest and most detailed study to date on the coagulation profiles in VA and VV ECMO patients, and confirm substantial differences between VA and VV coagulation profiles suggesting that coagulation management should be considered different between the two modalities.
A pattern of consumptive coagulopathy was present in VA patients; characterised by elevated d-dimers, bilirubin and lactate and prolonged prothrombin time and lower fibrinogen and platelet levels, decreased clot strength and platelet dysfunction. Further, VA patients received lower doses of heparin than VV patients to achieve similar aPTT levels, and had longer CK-R time but shorter CKH-R times by thromboelastography. These findings indicate that VA ECMO patients have higher consumption of clotting factors than VV patients, and that aPTT is a less reliable monitor of heparin therapy than in this group.
The differences in coagulation profile between VA and VV patients is likely in large part, to be explained by the differing baseline patient characteristics and underlying pathologies requiring support. VA patients with inherent cardiac dysfunction and periods of poor end-organ perfusion and liver dysfunction prior to, and during implementation of extracorporeal support may exhibit decreased coagulation factor production14. Moreover, 10 of our 19 VA patients received ECPR for cardiac arrest. Cardiac arrest results in systemic inflammation, increased coagulation factor consumption, disseminated intravascular coagulation (DIC), induction of tissue factor-dependent coagulation, impaired anticoagulant mechanisms15,16 and increased fibrinolysis16. Whilst the large proportion of ECPR patients in the VA group may contributed to some of differences when compared to VV patients, comparing non-ECPR VA patients to VV patients on subgroup analysis, differences in key parameters remained, thus supporting underlying differences between VA and VV patients independent of cardiac arrest status. Whilst cardiogenic shock with organ failure and a consumptive process appears to predominate in VA patients, ARDS patients typically exhibit an extreme inflammatory response with diffuse fibrin deposition17, a pro-coagulant response18 and massive thrombin generation17—differing underlying pathological processes.
Interestingly, significant differences were also seen between ECPR and non-ECPR patients in fibrinogen levels and lactate levels. This may be due to a more pronounced acute coagulative response in arrest patients.
We found lower indices of clot strength in with VA patients compared to VV patients with lower TEG Maximum Amplitude (MA); and lower G-value (a marker of overall platelet and fibrin performance). Low clot strength is predictive of bleeding events19 and a TEG CK G value below < 5 dynes/cm2 (as found in in our VA patients) is associated with increased risk of hemorrhage20. Our testing could not determine the relative contribution of hypofibrinogenemia, anti-platelet medication, intrinsic platelet dysfunction, and abnormal vWF on the abnormal clot strength.
Whilst hypofibrinogenemia and transient reduction in fibrinogen levels21 have been reported, many studies report normal or supranormal fibrinogen levels during ECMO19,21,22 (as we report in our VV patients) with an acute phase reaction from systemic inflammation in ARDS patients a likely contributor16. The decreased clot strength we found in our VA patients may have been caused by hypofibrinogenemia due to increased consumption and was most pronounced in ECPR patients presumably due to increased consumptive or fibrinolytic processes16.
We assessed platelet function with TEG Platelet Mapping and Multiplate Aggregometry and found that VA ECMO patients had significantly lower ADP activity and a trend to lower activity on TRAPtest results. ECMO related platelet dysfunction assessed by Multiplate aggregometry has been described previously in VV and VA ECMO patients23,24,25. Proposed mechanisms for this include: depletion of the stored platelet ADP26, sheer flow induced shedding of platelet adhesion glycoproteins27, loss of high molecular weight VWF multimers (HMWM) with reduced vWF activity28,29,30 and lower levels of platelet aggregation27,28,31,32. However, thrombocytopenia influences platelet function testing and some studies24,25 have not corrected for this. Balle et al. found no dysfunction compared to controls when results were corrected for platelet levels33. Thrombocytopenia, seen in our study, is common in both ECMO modalities34,35,36. Pre-ECMO platelet levels and development of critical illness may contribute to the its development37 more than duration of ECMO support and this may explain our finding of lower platelet count in VA compared to VV patients.
Relative thrombin generation in ECMO patients is only just being elucidated. Only one previous study of thrombin generation in VA patients has been reported38. Our study, is the first to look at residual thrombin generation in the presence of heparin effect during standard care in ECMO patients and demonstrates differences between VA and VV cohorts in response to UFH. Despite the expected large thrombin generation seen in ARDS patients on VV, our data suggested that VV patients were more likely to achieve thrombin suppression with lower anti-FXa levels than VA. The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation40. Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.
In heparinised patients demonstrating residual thrombin generation activity, anti-FXa levels, but not APTT, correlated with classical markers of thrombin generation indicating that anti-FXa may offer a more accurate method of guiding heparin dose, highlighted by the high variability in APTT at similar thrombin generation levels seen in the VA patients. In combination with our data showing the poor correlation between total heparin dose and aPTT, these results add to the literature suggesting that a randomised comparison between anti-FXa and aPTT as methods for adjusting UFH dosing in ECMO may be warranted. Clinical adjustments to monitoring UFH and changes to target ranges may also need to take in account inherent differences in VV versus VA patients in relationships between anti-FXa, aPTT levels and residual thrombin generation.
In our study only about one half of aPTT values were within prescribed range. This number is lower than documented in previous prospective randomised studies41 but higher than other cohort studies42 and reflects the difficulty in accurately titrating heparin in ECMO patients. VA patients had a higher proportion of aPTTs above the therapeutic range despite lower total heparin dosage and anti-FXa levels. A majority of very high aPTT (> 100 secs) values occurred in the first 24 h after initiation of ECMO support (especially in VA cases), most likely when these patient’s coagulation profiles are most deranged, and when they are more likely to have received bolus heparin doses for interventions (such as coronary angiography). High mean aPTT and level at 24 h post ECMO cannulation has been shown to be predi
ECMO patients exhibit a range of coagulation abnormalities including: consumption of both procoagulant and anticoagulant factors10,11, thrombocytopenia, altered vWF multimers12, platelet dysfunction1, decreased anti-thrombin2, as well as increased D-dimer, prothrombin fragment 1.2 and thrombin-antithrombin complexes13. Despite patients who require VA and VV ECMO support having substantially different characteristics and underlying pathologies, data on differences in underlying coagulation profiles is extremely limited and patients are often treated with the same anticoagulation protocols. Herein, using multiple measures of coagulation, we report the largest and most detailed study to date on the coagulation profiles in VA and VV ECMO patients, and confirm substantial differences between VA and VV coagulation profiles suggesting that coagulation management should be considered different between the two modalities.
A pattern of consumptive coagulopathy was present in VA patients; characterised by elevated d-dimers, bilirubin and lactate and prolonged prothrombin time and lower fibrinogen and platelet levels, decreased clot strength and platelet dysfunction. Further, VA patients received lower doses of heparin than VV patients to achieve similar aPTT levels, and had longer CK-R time but shorter CKH-R times by thromboelastography. These findings indicate that VA ECMO patients have higher consumption of clotting factors than VV patients, and that aPTT is a less reliable monitor of heparin therapy than in this group.
The differences in coagulation profile between VA and VV patients is likely in large part, to be explained by the differing baseline patient characteristics and underlying pathologies requiring support. VA patients with inherent cardiac dysfunction and periods of poor end-organ perfusion and liver dysfunction prior to, and during implementation of extracorporeal support may exhibit decreased coagulation factor production14. Moreover, 10 of our 19 VA patients received ECPR for cardiac arrest. Cardiac arrest results in systemic inflammation, increased coagulation factor consumption, disseminated intravascular coagulation (DIC), induction of tissue factor-dependent coagulation, impaired anticoagulant mechanisms15,16 and increased fibrinolysis16. Whilst the large proportion of ECPR patients in the VA group may contributed to some of differences when compared to VV patients, comparing non-ECPR VA patients to VV patients on subgroup analysis, differences in key parameters remained, thus supporting underlying differences between VA and VV patients independent of cardiac arrest status. Whilst cardiogenic shock with organ failure and a consumptive process appears to predominate in VA patients, ARDS patients typically exhibit an extreme inflammatory response with diffuse fibrin deposition17, a pro-coagulant response18 and massive thrombin generation17—differing underlying pathological processes.
Interestingly, significant differences were also seen between ECPR and non-ECPR patients in fibrinogen levels and lactate levels. This may be due to a more pronounced acute coagulative response in arrest patients.
We found lower indices of clot strength in with VA patients compared to VV patients with lower TEG Maximum Amplitude (MA); and lower G-value (a marker of overall platelet and fibrin performance). Low clot strength is predictive of bleeding events19 and a TEG CK G value below < 5 dynes/cm2 (as found in in our VA patients) is associated with increased risk of hemorrhage20. Our testing could not determine the relative contribution of hypofibrinogenemia, anti-platelet medication, intrinsic platelet dysfunction, and abnormal vWF on the abnormal clot strength.
Whilst hypofibrinogenemia and transient reduction in fibrinogen levels21 have been reported, many studies report normal or supranormal fibrinogen levels during ECMO19,21,22 (as we report in our VV patients) with an acute phase reaction from systemic inflammation in ARDS patients a likely contributor16. The decreased clot strength we found in our VA patients may have been caused by hypofibrinogenemia due to increased consumption and was most pronounced in ECPR patients presumably due to increased consumptive or fibrinolytic processes16.
We assessed platelet function with TEG Platelet Mapping and Multiplate Aggregometry and found that VA ECMO patients had significantly lower ADP activity and a trend to lower activity on TRAPtest results. ECMO related platelet dysfunction assessed by Multiplate aggregometry has been described previously in VV and VA ECMO patients23,24,25. Proposed mechanisms for this include: depletion of the stored platelet ADP26, sheer flow induced shedding of platelet adhesion glycoproteins27, loss of high molecular weight VWF multimers (HMWM) with reduced vWF activity28,29,30 and lower levels of platelet aggregation27,28,31,32. However, thrombocytopenia influences platelet function testing and some studies24,25 have not corrected for this. Balle et al. found no dysfunction compared to controls when results were corrected for platelet levels33. Thrombocytopenia, seen in our study, is common in both ECMO modalities34,35,36. Pre-ECMO platelet levels and development of critical illness may contribute to the its development37 more than duration of ECMO support and this may explain our finding of lower platelet count in VA compared to VV patients.
Relative thrombin generation in ECMO patients is only just being elucidated. Only one previous study of thrombin generation in VA patients has been reported38. Our study, is the first to look at residual thrombin generation in the presence of heparin effect during standard care in ECMO patients and demonstrates differences between VA and VV cohorts in response to UFH. Despite the expected large thrombin generation seen in ARDS patients on VV, our data suggested that VV patients were more likely to achieve thrombin suppression with lower anti-FXa levels than VA. The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation40. Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.
In heparinised patients demonstrating residual thrombin generation activity, anti-FXa levels, but not APTT, correlated with classical markers of thrombin generation indicating that anti-FXa may offer a more accurate method of guiding heparin dose, highlighted by the high variability in APTT at similar thrombin generation levels seen in the VA patients. In combination with our data showing the poor correlation between total heparin dose and aPTT, these results add to the literature suggesting that a randomised comparison between anti-FXa and aPTT as methods for adjusting UFH dosing in ECMO may be warranted. Clinical adjustments to monitoring UFH and changes to target ranges may also need to take in account inherent differences in VV versus VA patients in relationships between anti-FXa, aPTT levels and residual thrombin generation.
In our study only about one half of aPTT values were within prescribed range. This number is lower than documented in previous prospective randomised studies41 but higher
ECMO patients exhibit a range of coagulation abnormalities including: consumption of both procoagulant and anticoagulant factors10,11, thrombocytopenia, altered vWF multimers12, platelet dysfunction1, decreased anti-thrombin2, as well as increased D-dimer, prothrombin fragment 1.2 and thrombin-antithrombin complexes13. Despite patients who require VA and VV ECMO support having substantially different characteristics and underlying pathologies, data on differences in underlying coagulation profiles is extremely limited and patients are often treated with the same anticoagulation protocols. Herein, using multiple measures of coagulation, we report the largest and most detailed study to date on the coagulation profiles in VA and VV ECMO patients, and confirm substantial differences between VA and VV coagulation profiles suggesting that coagulation management should be considered different between the two modalities.
A pattern of consumptive coagulopathy was present in VA patients; characterised by elevated d-dimers, bilirubin and lactate and prolonged prothrombin time and lower fibrinogen and platelet levels, decreased clot strength and platelet dysfunction. Further, VA patients received lower doses of heparin than VV patients to achieve similar aPTT levels, and had longer CK-R time but shorter CKH-R times by thromboelastography. These findings indicate that VA ECMO patients have higher consumption of clotting factors than VV patients, and that aPTT is a less reliable monitor of heparin therapy than in this group.
The differences in coagulation profile between VA and VV patients is likely in large part, to be explained by the differing baseline patient characteristics and underlying pathologies requiring support. VA patients with inherent cardiac dysfunction and periods of poor end-organ perfusion and liver dysfunction prior to, and during implementation of extracorporeal support may exhibit decreased coagulation factor production14. Moreover, 10 of our 19 VA patients received ECPR for cardiac arrest. Cardiac arrest results in systemic inflammation, increased coagulation factor consumption, disseminated intravascular coagulation (DIC), induction of tissue factor-dependent coagulation, impaired anticoagulant mechanisms15,16 and increased fibrinolysis16. Whilst the large proportion of ECPR patients in the VA group may contributed to some of differences when compared to VV patients, comparing non-ECPR VA patients to VV patients on subgroup analysis, differences in key parameters remained, thus supporting underlying differences between VA and VV patients independent of cardiac arrest status. Whilst cardiogenic shock with organ failure and a consumptive process appears to predominate in VA patients, ARDS patients typically exhibit an extreme inflammatory response with diffuse fibrin deposition17, a pro-coagulant response18 and massive thrombin generation17—differing underlying pathological processes.
Interestingly, significant differences were also seen between ECPR and non-ECPR patients in fibrinogen levels and lactate levels. This may be due to a more pronounced acute coagulative response in arrest patients.
We found lower indices of clot strength in with VA patients compared to VV patients with lower TEG Maximum Amplitude (MA); and lower G-value (a marker of overall platelet and fibrin performance). Low clot strength is predictive of bleeding events19 and a TEG CK G value below < 5 dynes/cm2 (as found in in our VA patients) is associated with increased risk of hemorrhage20. Our testing could not determine the relative contribution of hypofibrinogenemia, anti-platelet medication, intrinsic platelet dysfunction, and abnormal vWF on the abnormal clot strength.
Whilst hypofibrinogenemia and transient reduction in fibrinogen levels21 have been reported, many studies report normal or supranormal fibrinogen levels during ECMO19,21,22 (as we report in our VV patients) with an acute phase reaction from systemic inflammation in ARDS patients a likely contributor16. The decreased clot strength we found in our VA patients may have been caused by hypofibrinogenemia due to increased consumption and was most pronounced in ECPR patients presumably due to increased consumptive or fibrinolytic processes16.
We assessed platelet function with TEG Platelet Mapping and Multiplate Aggregometry and found that VA ECMO patients had significantly lower ADP activity and a trend to lower activity on TRAPtest results. ECMO related platelet dysfunction assessed by Multiplate aggregometry has been described previously in VV and VA ECMO patients23,24,25. Proposed mechanisms for this include: depletion of the stored platelet ADP26, sheer flow induced shedding of platelet adhesion glycoproteins27, loss of high molecular weight VWF multimers (HMWM) with reduced vWF activity28,29,30 and lower levels of platelet aggregation27,28,31,32. However, thrombocytopenia influences platelet function testing and some studies24,25 have not corrected for this. Balle et al. found no dysfunction compared to controls when results were corrected for platelet levels33. Thrombocytopenia, seen in our study, is common in both ECMO modalities34,35,36. Pre-ECMO platelet levels and development of critical illness may contribute to the its development37 more than duration of ECMO support and this may explain our finding of lower platelet count in VA compared to VV patients.
Relative thrombin generation in ECMO patients is only just being elucidated. Only one previous study of thrombin generation in VA patients has been reported38. Our study, is the first to look at residual thrombin generation in the presence of heparin effect during standard care in ECMO patients and demonstrates differences between VA and VV cohorts in response to UFH. Despite the expected large thrombin generation seen in ARDS patients on VV, our data suggested that VV patients were more likely to achieve thrombin suppression with lower anti-FXa levels than VA. The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation40. Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.
In heparinised patients demonstrating residual thrombin generation activity, anti-FXa levels, but not APTT, correlated with classical markers of thrombin generation indicating that anti-FXa may offer a more accurate method of guiding heparin dose, highlighted by the high variability in APTT at similar thrombin generation levels seen in the VA patients. In combination with our data showing the poor correlation between total heparin dose and aPTT, these results add to the literature suggesting that a randomised comparison between anti-FXa and aPTT as methods for adjusting UFH dosing in ECMO may be warranted. Clinical adjustments to monitoring UFH and changes to target ranges may also need to take in account inherent differences in VV versus VA patients in relationships between anti-FXa, aPTT levels and residual thrombin generation.
In our study only about one half of aPTT values were within prescribed range. This number is lower than documented in previous prospective randomised studies41 but higher than other cohort studies42 and reflects the difficulty in accurately titrating heparin in ECMO patients. VA patients had a higher proportion of aPTTs above the therapeutic range despite lower total heparin dosage and anti-FXa levels. A majority of very high aPTT (> 100 secs) values occurred in the first 24 h after initiation of ECMO support (especially in VA cases), most likely when these patient’s coagulation profiles are most deranged, and when they are more likely to have received bolus hep
ECMO patients exhibit a range of coagulation abnormalities including: consumption of both procoagulant and anticoagulant factors10,11, thrombocytopenia, altered vWF multimers12, platelet dysfunction1, decreased anti-thrombin2, as well as increased D-dimer, prothrombin fragment 1.2 and thrombin-antithrombin complexes13. Despite patients who require VA and VV ECMO support having substantially different characteristics and underlying pathologies, data on differences in underlying coagulation profiles is extremely limited and patients are often treated with the same anticoagulation protocols. Herein, using multiple measures of coagulation, we report the largest and most detailed study to date on the coagulation profiles in VA and VV ECMO patients, and confirm substantial differences between VA and VV coagulation profiles suggesting that coagulation management should be considered different between the two modalities.
A pattern of consumptive coagulopathy was present in VA patients; characterised by elevated d-dimers, bilirubin and lactate and prolonged prothrombin time and lower fibrinogen and platelet levels, decreased clot strength and platelet dysfunction. Further, VA patients received lower doses of heparin than VV patients to achieve similar aPTT levels, and had longer CK-R time but shorter CKH-R times by thromboelastography. These findings indicate that VA ECMO patients have higher consumption of clotting factors than VV patients, and that aPTT is a less reliable monitor of heparin therapy than in this group.
The differences in coagulation profile between VA and VV patients is likely in large part, to be explained by the differing baseline patient characteristics and underlying pathologies requiring support. VA patients with inherent cardiac dysfunction and periods of poor end-organ perfusion and liver dysfunction prior to, and during implementation of extracorporeal support may exhibit decreased coagulation factor production14. Moreover, 10 of our 19 VA patients received ECPR for cardiac arrest. Cardiac arrest results in systemic inflammation, increased coagulation factor consumption, disseminated intravascular coagulation (DIC), induction of tissue factor-dependent coagulation, impaired anticoagulant mechanisms15,16 and increased fibrinolysis16. Whilst the large proportion of ECPR patients in the VA group may contributed to some of differences when compared to VV patients, comparing non-ECPR VA patients to VV patients on subgroup analysis, differences in key parameters remained, thus supporting underlying differences between VA and VV patients independent of cardiac arrest status. Whilst cardiogenic shock with organ failure and a consumptive process appears to predominate in VA patients, ARDS patients typically exhibit an extreme inflammatory response with diffuse fibrin deposition17, a pro-coagulant response18 and massive thrombin generation17—differing underlying pathological processes.
Interestingly, significant differences were also seen between ECPR and non-ECPR patients in fibrinogen levels and lactate levels. This may be due to a more pronounced acute coagulative response in arrest patients.
We found lower indices of clot strength in with VA patients compared to VV patients with lower TEG Maximum Amplitude (MA); and lower G-value (a marker of overall platelet and fibrin performance). Low clot strength is predictive of bleeding events19 and a TEG CK G value below < 5 dynes/cm2 (as found in in our VA patients) is associated with increased risk of hemorrhage20. Our testing could not determine the relative contribution of hypofibrinogenemia, anti-platelet medication, intrinsic platelet dysfunction, and abnormal vWF on the abnormal clot strength.
Whilst hypofibrinogenemia and transient reduction in fibrinogen levels21 have been reported, many studies report normal or supranormal fibrinogen levels during ECMO19,21,22 (as we report in our VV patients) with an acute phase reaction from systemic inflammation in ARDS patients a likely contributor16. The decreased clot strength we found in our VA patients may have been caused by hypofibrinogenemia due to increased consumption and was most pronounced in ECPR patients presumably due to increased consumptive or fibrinolytic processes16.
We assessed platelet function with TEG Platelet Mapping and Multiplate Aggregometry and found that VA ECMO patients had significantly lower ADP activity and a trend to lower activity on TRAPtest results. ECMO related platelet dysfunction assessed by Multiplate aggregometry has been described previously in VV and VA ECMO patients23,24,25. Proposed mechanisms for this include: depletion of the stored platelet ADP26, sheer flow induced shedding of platelet adhesion glycoproteins27, loss of high molecular weight VWF multimers (HMWM) with reduced vWF activity28,29,30 and lower levels of platelet aggregation27,28,31,32. However, thrombocytopenia influences platelet function testing and some studies24,25 have not corrected for this. Balle et al. found no dysfunction compared to controls when results were corrected for platelet levels33. Thrombocytopenia, seen in our study, is common in both ECMO modalities34,35,36. Pre-ECMO platelet levels and development of critical illness may contribute to the its development37 more than duration of ECMO support and this may explain our finding of lower platelet count in VA compared to VV patients.
Relative thrombin generation in ECMO patients is only just being elucidated. Only one previous study of thrombin generation in VA patients has been reported38. Our study, is the first to look at residual thrombin generation in the presence of heparin effect during standard care in ECMO patients and demonstrates differences between VA and VV cohorts in response to UFH. Despite the expected large thrombin generation seen in ARDS patients on VV, our data suggested that VV patients were more likely to achieve thrombin suppression with lower anti-FXa levels than VA. The overall increased thrombin generation found in our VA patients likely reflect lower total heparin doses and lower anti-thrombin levels when compared to VV patients. Anti-thrombin deficiency, especially within the initial days of support, is commonly reported in ECMO patients39 and is suspected to be caused by due to activation of coagulation, impaired synthesis, increased fibrinolysis and disseminated intravascular coagulation40. Future studies may be able to elucidate if this is related to variation in anti-thrombin consumption.
In heparinised patients demonstrating residual thrombin generation activity, anti-FXa levels, but not APTT, correlated with classical markers of thrombin generation indicating that anti-FXa may offer a more accurate method of guiding heparin dose, highlighted by the high variability in APTT at similar thrombin generation levels seen in the VA patients. In combination with our data showing the poor correlation between total heparin dose and aPTT, these results add to the literature suggesting that a randomised comparison between anti-FXa and aPTT as methods for adjusting UFH dosing in ECMO may be warranted. Clinical adjustments to monitoring UFH and changes to target ranges may also need to take in account inherent differences in VV versus VA patients in relationships between anti-FXa, aPTT levels and residual thrombin generation.
In our study only about one half of aPTT values were within prescribed range. This number is lower than documented in previous prospective randomised studies41 but higher than other cohort studies42 and reflects the difficulty in accurately titrating heparin in ECMO patients. VA patients had a higher proportion of aPTTs above the therapeutic range despite lower total heparin dosage and anti-FXa levels. A majority of very high aPTT (> 100 secs) values occurred in the first 24 h after initiation of ECMO support (especially in VA cases), most likely when these patient’s coagulation profiles are most deranged, and when they are more likely to have received bolus hep
arin doses for interventions (such as coronary angiography). High mean aPTT and level at 24 h post ECMO cannulation has been shown to be predictive of bleeding events4,43. Our finding that all major VA bleeding events within this time, (compared to Day 4 on VV ECMO patients) reinforces the need for meticulous anticoagulation management during this time.
arin doses for interventions (such as coronary angiography). High mean aPTT and level at 24 h post ECMO cannulation has been shown to be predictive of bleeding events4,43. Our finding that all major VA bleeding events within this time, (compared to Day 4 on VV ECMO patients) reinforces the need for meticulous anticoagulation management during this time.
than other cohort studies42 and reflects the difficulty in accurately titrating heparin in ECMO patients. VA patients had a higher proportion of aPTTs above the therapeutic range despite lower total heparin dosage and anti-FXa levels. A majority of very high aPTT (> 100 secs) values occurred in the first 24 h after initiation of ECMO support (especially in VA cases), most likely when these patient’s coagulation profiles are most deranged, and when they are more likely to have received bolus heparin doses for interventions (such as coronary angiography). High mean aPTT and level at 24 h post ECMO cannulation has been shown to be predictive of bleeding events4,43. Our finding that all major VA bleeding events within this time, (compared to Day 4 on VV ECMO patients) reinforces the need for meticulous anticoagulation management during this time.
ctive of bleeding events4,43. Our finding that all major VA bleeding events within this time, (compared to Day 4 on VV ECMO patients) reinforces the need for meticulous anticoagulation management during this time.
jority of very high aPTT (> 100 secs) values occurred in the first 24 h after initiation of ECMO support (especially in VA cases), most likely when these patient’s coagulation profiles are most deranged, and when they are more likely to have received bolus heparin doses for interventions (such as coronary angiography). High mean aPTT and level at 24 h post ECMO cannulation has been shown to be predictive of bleeding events4,43. Our finding that all major VA bleeding events within this time, (compared to Day 4 on VV ECMO patients) reinforces the need for meticulous anticoagulation management during this time.
majority of very high aPTT (> 100 secs) values occurred in the first 24 h after initiation of ECMO support (especially in VA cases), most likely when these patient’s coagulation profiles are most deranged, and when they are more likely to have received bolus heparin doses for interventions (such as coronary angiography). High mean aPTT and level at 24 h post ECMO cannulation has been shown to be predictive of bleeding events4,43. Our finding that all major VA bleeding events within this time, (compared to Day 4 on VV ECMO patients) reinforces the need for meticulous anticoagulation management during this time.
Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: the HECTIC study
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