Evidence of altered haemostasis in an ovine model of venovenous extracorporeal membrane oxygenation support

Abstract

BackgroundExtracorporeal membrane oxygenation (ECMO) is a life-saving modality used in the management of cardiopulmonary failure that is refractory to conventional medical and surgical therapies. The major problems clinicians face are bleeding and clotting, which can occur simultaneously. To discern the impact of pulmonary injury and ECMO on the host’s haemostatic response, we developed an ovine model of smoke-induced acute lung injury (S-ALI) and ECMO. The aims of this study were to determine if the ECMO circuit itself altered haemostasis and if this was augmented in a host with pulmonary injury.MethodsTwenty-seven South African meat merino/Border Leicester Cross ewes underwent instrumentation. Animals received either sham injury (n = 12) or S-ALI (n = 15). Control animal groups consisted of healthy controls (ventilation only for 24 h) (n = 4), ECMO controls (ECMO only for 24 h) (n = 8) and S-ALI controls (S-ALI but no ECMO for 24 h) (n = 7). The test group comprised S-ALI sheep placed on ECMO (S-ALI + ECMO for 24 h) (n = 8). Serial blood samples were taken for rotational thromboelastometry, platelet aggregometry and routine coagulation laboratory tests. Animals were continuously monitored for haemodynamic, fluid and electrolyte balances and temperature. Pressure-controlled intermittent mandatory ventilation was used, and mean arterial pressure was augmented by protocolised use of pressors, inotropes and balanced fluid resuscitation to maintain mean arterial pressure >65 mmHg.ResultsRotational thromboelastometry, platelet aggregometry and routine coagulation laboratory tests demonstrated that S-ALI and ECMO independently induced changes to platelet function, delayed clot formation and reduced clot firmness. This effect was augmented with the combination of S-ALI and ECMO, with evidence of increased collagen-induced platelet aggregation as well as changes in factor VIII (FVIII), factor XII and fibrinogen levels.ConclusionsThe introduction of an ECMO circuit itself increases collagen-induced platelet aggregation, decreases FVIII and von Willebrand factor, and induces a transient decrease in fibrinogen levels and function in the first 24 h. These changes to haemostasis are amplified when a host with a pre-existing pulmonary injury is placed on ECMO. Because patients are often on ECMO for extended periods, longer-duration studies are required to characterise ECMO-induced haemostatic changes over the long term. The utility of point-of-care tests for guiding haemostatic management during ECMO also warrants further exploration.

Current Understanding of How Extracorporeal Membrane Oxygenators Activate Haemostasis and Other Blood Components

“…These include the coagulation factors of the contact activation pathway—high molecular weight kininogen (HMWK) and factor XII–as well as high-density lipoprotein (HDL), albumin, immunoglobin G (IgG), and complement component C3 (14). It has been shown by Passmore et al that fibrinogen levels fall in an ovine lung injury model with the commencement of the ECMO circuit and recover to the baseline level within 48 h in keeping with its adhesion to the biosurface and loss from circulation (15). We have also observed this acquired hypofibrinogenaemia in pediatrics following CPB with increased hemorrhage and reduced clot strength (16).…”

“…Factor VIII is an acute phase molecule that is significantly elevated in pro-inflammatory states. Passmore et al showed that FVIII falls in both a lung-injury model and control-animal models on ECMO circuits than those without after 24 h by over 50% (15). This was concurrently noted to be with lower fibrinogen and von Willebrand factor (VWF) levels suggestive of increased consumption of FVIII or decreased VWF-binding ability.…”

Hemostatic Management of Extracorporeal Circuits Including Cardiopulmonary Bypass and Extracorporeal Membrane Oxygenation

“…77 However, the etiology of hypofibrinogenemia can be multifactorial, such as dilutional effect due to large extracorporeal volume requiring saline or red cell prime, underlying conditions such as sepsis and liver failure, increased consumption due to thrombosis, disseminated intravascular coagulation (DIC), and hyperfibrinolysis. 78,79 Whole blood testing with viscoelastic hemostatic assays (ROTEM or TEG) can be used in identifying severe hyperfibrinolysis. 80 The mechanism of fibrinolysis in ECMO patients is not very clear and probably involves multiple mechanisms, one being secondary fibrinolysis, in which the production of thrombin stimulates release of tPA from endothelial cells.…”

Clinical complications during veno-arterial extracorporeal membrane oxigenation in post-cardiotomy and non post-cardiotomy shock: still the achille’s heel

“…Another study proved in an ovine model that the ECMO therapy increases collagen-induced platelet aggregation, decreases factor VIII and von Willebrand factor; then it defines a decrease of fibrinogen levels and an alteration function in the first 24 hours (29).…”

“…Due to the critical state of patients suited for its use and the extracorporeal circuit itself, ECMO carries several possible complications that can have a relevant impact on the immediate and remote outcomes. A correct prevention and [39] 848 [29] ECLS, extracorporeal life support; ECPR, ECLS to support cardiopulmonary resuscitation. an early recognition of specific signs can help to reduce the incidence of adverse events (23,35,36) ( Figure 2).…”