Optimizing Anticoagulation Therapy during ECMO: Strategies and Monitoring

5. Systemic anticoagulation during ECMO is intended to control thrombin generation and limit the risk for thrombotic and hemorrhagic complications. Unfractionated heparin (UFH) is the most commonly used anticoagulant. UFH acts by binding and inactivating factor Xa and thrombin. UFH increases the kinetic of the natural thrombin-antithrombin binding by 2,000–4,000 times.

6. As a consequence, chronic heparin administration consumes the endothelial and circulating pool of AT. Additionally, heparin may be bound and inactivated by plasma proteins, endothelial surface, and most of all by circulating platelets, which scavenge heparin by releasing PF4. Due to this complex scenario, the exact dose required to correctly blunt thrombin generation is undefined and may greatly vary during the course of an ECMO. The classical dose range is reported between 20 and 70 IU/kg/h. AT and number of platelets variations may profoundly vary the sensitivity to UFH. This leads to the need for continuous adjustments of the UFH dose, even if in general there is a trend for larger doses the longer the ECMO system is in place

7. The classical dose range is reported between 20 and 70 IU/kg/h. No-anticoagulation-based ECMO is a strategy may be considered in case of excessive bleeding risk, like for trauma patients. To achieve peripheral vessels cannulation, a small (50–100 IU/kg) bolus dose of heparin is usually administered. In postcardiotomy ECMO, full heparinization is usually already achieved. After cannulation and onset of ECMO, heparin should be fully antagonized with protamine sulfate. Subsequently, given the residual effects of CPB and surgery, no heparinization is usually undertaken for the first 12–24 h, to avoid massive postoperative bleeding. Once bleeding is under control, heparin infusion should be started at a low dose (20 IU/kg/h) and subsequently adjusted to the desired level of anticoagulation.

8. Alternatives to Heparin Bivalirudin is a direct thrombin inhibitor with a short half-life of about 25 min and partial (20 %) kidney clearance The dose of bivalirudin is usually reported around 0.03–0.2 mg/kg/h, with or without an initial bolus of 0.5 mg/kg Other direct thrombin inhibitors proposed for ECMO in case of HIT include argatroban (0.1–0.4 μg/kg/min) while danaparoid and lepirudin have been used in the past but are presently abandoned.

9. AT Inevitably, AT is consumed during ECMO, and the majority of the authors suggest purified AT supplementation aimed to maintain AT activity at the lower normal range of 70 % Of notice, when bivalirudin is used, AT consumption is strongly limited, albeit present

10. Monitoring the Hemostatic System During ECMO Activated Clotting Time (ACT) ACT remains the standard of monitoring during heparin anticoagulation in ECMO. The ACT provides a bedside assessment of the intrinsic and common pathway integrity. During ECMO, the ACT is usually maintained between 180 and 220 s

11. Conventional Laboratory Tests Activated partial thromboplastin time (APTT) explores the intrinsic and common pathways of coagulation and is the classical measure for heparin therapy. An APTT of 1.5 times the baseline APTT (50–80 s) is considered the target value during ECMO and corresponds to a heparin concentration of 0.2–0.3 IU/mL. Prothrombin time (PT) is a marker of the extrinsic and common coagulation pathways and should be performed in order to detect the level of coagulation factors and to guide their supplementation with fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), or cryoprecipitates. Platelet count, fibrinogen levels, and d -dimers assays should be performed daily.

12. Thromboelastography and Thromboelastometry The r time and coagulation time are surrogates for thrombin generation and may guide the UFH infusion rate during ECMO. There is not a universally accepted value of r time for optimal UFH dose, but the majority of the authors report an optimal window between two and three times the upper normal limit (16–25 min)

13. The anti-Xa UFH assay measures the anti-Xa activity of heparin in plasma. An optimal value, corresponding to an APTT 1.5–2 times the baseline, is between 0.3 and 0.7 IU/mL. At present, there is a gap in knowledge about platelet function and antiplatelet drugs use during ECMO.

14. Adjusting the Coagulation Profile Guiding the patient into the framework of this optimal pattern is one of the most tricky steps during an ECMO management. UFH or bivalirudin dose should be adjusted based on ACT, APTT, and TEG/TEM. The other issues can be adjusted using allogeneic blood products or substitutes. Purified AT is available for AT supplementation. A severe gap in plasma coagulation factors (INR >3) can be corrected with PCC or cryoprecipitates, whereas minor gaps (INR 2–3) could even be treated with FFP. Suggested values of fibrinogen should be at least 100 g/dL, which approximately correspond to a maximum clot firmness >10 mm at TEM. Fibrinogen concentrate is available for supplementation;

15. Antifibrinolytic therapy with epsilon-aminocaproic acid or tranexamic acid should be initiated in presence of signs of ongoing hyperfibrinolysis at TEG/TEM or conventional tests. A certain degree of fibrinolysis is always present during ECMO; values of d -dimers around 300 μg/L are acceptable, but signs of progressive increase suggest a prompt intervention. Platelet count should be maintained above 80,000 cells/mmc in a patient with active bleeding or at high risk for bleeding, with platelet concentrate transfusions. Conversely, lower values (however >45,000 cells/mmc) may be accepted in non bleeding patients or patients at low risk for bleeding. Finally, red blood cells should be administered to maintain a hemoglobin level at a minimal value of 8 g/dL; A bleeding patient requires a prompt and aggressive approach, with allogeneic blood products and substitutes therapy guided by the whole set of coagulation tests. Conversely, a non-bleeding patient should be treated more conservatively, trying not to treat numbers instead of the patient