Clinical trial NCT06868823: Prospective Observational Pilot Study of LMWH Versus UFH as ECMO Anticoagulation in Lung Transplantation
Official title: LMWH Versus UFH as ECMO Anticoagulation in Lung Transplantation: A Prospective, Observational, and Pilot Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Lung Transplantation
Extracorporeal Membrane Oxygenation (ECMO)
Anticoagulants and Bleeding Disorders
Keywords: Lung Transplantation
Extracorporeal Membrane Oxygenation (ECMO)
Anticoagulation
Low-Molecular-Weight Heparin (LMWH)
Unfractionated Heparin (UFH)
Thrombosis Prevention
Bleeding Complications
Coagulation Management in Surgery
Hemorrhagic and Thrombotic Events
Perioperative Hemostasis
Lead sponsor: University Hospital, Motol
Sponsor class: OTHER
First posted: 2025-03-11
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will consist of patients indicated for bilateral lung transplantation from the Czech Republic and Slovakia, who will undergo surgery at Motol Hospital in Prague.

Brief summary: The aim of this observational pilot study is to evaluate the effectiveness and safety of low-molecular-weight heparin (LMWH) compared to unfractionated heparin (UFH) as anticoagulation in perioperative ECMO during bilateral lung transplantation.

The main question this study seeks to answer is:

Does LMWH provide a safe and effective alternative to UFH for ECMO anticoagulation in lung transplantation, with reduced bleeding and thrombotic complications?

Patients undergoing bilateral lung transplantation with perioperative veno-arterial (V-A) ECMO support will be assigned to one of two anticoagulation strategies:

UFH group: Standard UFH anticoagulation monitored using ROTEM. LMWH group: Enoxaparin-based anticoagulation monitored using ROTEM. The study will assess perioperative blood loss, hemoglobin levels, transfusion needs, and thrombotic events. Additional analyses will include coagulation profile assessments using point-of-care (POC) tests, thrombin generation test (TGT), and laboratory coagulation parameters.

Detailed description: Introduction:

Extracorporeal circulation known as "extracorporeal membrane oxygenation" (ECMO) is a method of supportive therapy for terminal respiratory failure (1-3) or temporary replacement of lung function in the perioperative period during lung transplantation (4). In the former case, it is V-V ECMO (veno-venous ECMO), while in the latter case it is V-A ECMO (veno-arterial ECMO). According to the EURO-ELSO recommendations, the use of unfractionated heparin (UFH) is recommended as anticoagulation of the ECMO set (5). However, 40-50% of patients on ECMO experience not only bleeding but also thrombotic complications (6,7). Nowadays, there is an increasing number of case reports and small studies showing that UFH is not used and instead only standard thrombosis prophylaxis with low molecular weight heparin (LMWH) is administered without signs of thrombosis in the ECMO set (8,9). ECMO has been shown to cause impaired primary hemostasis, which can be detected by devices such as the PFA 200, ROTEM-Platelet, and Multiplate. The main pathology involves platelets and to a lesser extent von Willebrand factor (vWF) (10-12). The ECMO system is a high-flow "high shear stress" system that is comparable to the arterial circulation in vivo. In this setting, the so-called "white thrombus" plays a major role in thrombosis formation. Antiplatelet drugs are commonly used to prevent thrombosis in such a system, for example in cardiology and neurology. Thus, it can be assumed that ECMO-induced impairment of primary hemostasis, specifically impaired platelet plug formation, could naturally serve as a prevention of white thrombus formation and thrombosis of the ECMO set. However, prevention of thrombosis in the venous system or on the surface of ECMO cannulae, i.e., prevention of "red thrombus formation", is still necessary because of the existence of the Virchow triad. Since the main target of action of LMWH is factor FXa and the main target of UFH is mainly factor FIIa, it can be assumed that LMWH could be sufficient to prevent thrombosis, with minimal risk of bleeding. It is important to emphasize that LMWH only minimally blocks thrombin generation and affects the conversion of fibrinogen to fibrin only to a limited extent (i.e., thrombin time - TT), unlike UFH. Moreover, ROTEM testing can be used to monitor both UFH and LMWH (13-16). A recent study published by us supports this hypothesis and suggests that the use of LMWH in patients on ECMO support may represent a safe alternative to anticoagulation or thromboprophylaxis. The study shows that its use resulted in a relatively low incidence of bleeding and thrombotic complications (17). Thus, it can be assumed that LMWH will be suitable and effective for the prevention of thrombus formation with minimal risk of bleeding, even in patients undergoing lung transplantation with perioperative ECMO support. This hypothesis is supported by studies that have found that UFH leads to higher platelet activation compared with LMWH (18-20). On the other hand, the use of activated factor FVIIa at low doses of 12 µg/kg appears to be safe (without increasing thrombotic events) and effective in reducing postoperative bleeding in cardiac surgery. Since FVIIa acts at the site of damaged endothelium, it can be assumed that relatively small doses of FVIIa will be sufficient to stop bleeding, but not so high as to cause thrombosis. In addition, it can be assumed that isolated administration of this factor may be less thrombogenic compared with other preparations that also contain factors acting on the axes of the intrinsic clotting pathway, such as prothrombin complex concentrate (PCC, contains FII, FVII, FIX, FX) or Haemate P (contains vWF and FVIII). Therefore, early administration of low-dose FVIIa may represent an effective way to minimize perioperative blood loss without increasing the risk of thrombosis (21). Another property of recombinant activated FVIIa is its ability to positively affect platelet adhesion and aggregation, which is present during ECMO support (20,22).

Aim and nature of the study:

This is a pilot observational study to prospectively compare two groups of patients with different types of anticoagulation (LMWH vs. UFH) undergoing bilateral lung transplantation with perioperative V-A ECMO support.

Hypothesis:

The use of LMWH represents a safe alternative method of ECMO anticoagulation and thromboprophylaxis that reduces the rate of bleeding and thrombotic complications compared to the current method of anticoagulation with UFH.

Methodology:

The study was approved by the Ethics Committee of Motol University Hospital. All patients enrolled in the study will sign an informed consent for participation in the study and data collection. It will be explained to the patients that there are two types of anticoagulation that are currently standardly used at Motol Hospital for patients with ECMO support. The type of anticoagulation will be determined at the discretion of the anaesthesiologist, with the aim of dividing patients as evenly as possible into different groups. Two groups of patients with different types of anticoagulation (LMWH vs. UFH) will be compared. As this is a pilot project, a total of 40 patients will be included in the study, with each group comprising 20 patients.

In case of blood loss ≥ 500 ml and ongoing bleeding, i.e. "wet operating field", the following Motol University bleeding management protocol will be initiated in both UFH and LMWH group:

* investigate PFA 200 (Col/EPI) and ROTEM (EXTEM, INTEM, FIBTEM and HEPTEM)
* in case of pathology of PFA 200 and/or CT EXTEM/CT HEPTEM - administer Novoseven at 10-30 ug/kg (recombinant activated factor VIIa)
* re-examine all ROTEM tests (EXTEM, FIBTEM, HEPTEM) and if needed normalize them:
* CT-EXTEM \> 80s by administering PCC at 10-30 ug/kg
* normalise CT-HEPTEM \> 240s by administering Haemate P at 10-30j/kg
* for FIBTEM pathology - administer Exacyl at 10-30 mg/kg prior to Fibrinogen administration and normalize FIBTEM MCF ≤10 mm by administering Hemocompletan at 10-30 mg/kg - or more precisely: desired MCF - current MCF x 6.25 mg/kg e.g. (10 - 4) x (6.25 x 80 kg) = 3000 mg (add 0.5 g of fibrinogen per 1 mm)
* administer platelets at EXTEM MCF ≤ 50mm and FIBTEM MCF ≥ 10mm administer 5-10 mL/kg platelets (2 TU platelets from apheresis in an adult patient) or maintain platelets ≥ 50-100 x109/L
* if bleeding continues give Factor XIII - Fibrogammin at 10-30j/kg
* if PFA Col/EPI pathology persists and bleeding continues - give Haemate P at 20-40j/kg (if not already given to correct CT INTEM)
* if bleeding continues, repeat Novoseven 10-30 ug/kg every 4 hours for a total of 3 times
* if severe bleeding continues, give full dose of Novoseven 100 ug/kg
* if bleeding does not stop - discontinue anticoagulation/thromboprophylaxis

Note:

* for blood loss over 50% of blood volume, consider Octaplas or frozen plasma (in an adult patient with blood loss over 2000-3000 ml)
* maintain normal pH, calcium, magnesium, normothermia and haematocrit ≥0.3 (required for normal primary haemostasis)
* administer 5% albumin or transfusion products as above to maintain normovolemia (try to minimise intake of other colloids or crystalloids)

Statistical analysis:

statistical program GraphPad will be used, paired t-test, p \< 0.05

Eligibility criteria: Inclusion Criteria:

1. ⃣ Adults (≥18 years old).
2. ⃣ Patients undergoing bilateral lung transplantation with perioperative veno-arterial (V-A) ECMO support.
3. ⃣ Planned perioperative anticoagulation with either UFH or LMWH, as determined by the attending anesthesiologist.
4. ⃣ Ability to provide informed consent or consent provided by a legally authorized representative.

Exclusion Criteria:

1. ⃣ Patients receiving ECMO as a bridge to lung transplantation.
2. ⃣ Patients requiring postoperative continuation of ECMO.
3. ⃣ Patients with perioperative blood loss ≥3,000 mL.
4. ⃣ Patients undergoing lung re-transplantation.
5. ⃣ History of severe coagulopathy or bleeding disorder.
6. ⃣ Active use of antiplatelet or anticoagulant therapy (excluding study anticoagulants).
7. ⃣ Known heparin-induced thrombocytopenia (HIT).
8. ⃣ Severe liver dysfunction (Child-Pugh C) or end-stage renal disease requiring dialysis.
9. ⃣ Pregnant or breastfeeding women.

Primary outcomes:
measure: Perioperative Blood Loss
timeFrame: Measured intraoperatively, at the end of surgery.
measure: Change in Hemoglobin Levels during surgery and within 24 hours after surgery
timeFrame: Intraoperative: Change in hemoglobin from preoperative levels to the end of surgery. Postoperative: Change in hemoglobin from preoperative levels to 24 hours post-surgery.
measure: Blood Transfusion Requirements during surgery and Within 24 Hours after surgery
timeFrame: Intraoperative: PRBC transfusions administered during surgery. Postoperative: PRBC transfusions administered within the first 24 hours after surgery.
measure: Incidence of Thrombotic Complications during surhery and within 24 Hours postoperatively.
timeFrame: Intraoperative: Thrombotic events occurring during surgery. Postoperative: Thrombotic events occurring within 24 hours after surgery.
Secondary outcomes:
measure: Coagulation Profile Assessed by Point-of-Care (POC) Tests
timeFrame: Before anticoagulation administration; 5 minutes after anticoagulation; at ≥500 mL blood loss with ongoing bleeding "wet surgical field"; 5 minutes after NovoSeven (activated FVIIa); at end of surgery before ECMO explantation; upon ICU admission
measure: Coagulation Profile Assessed by Thrombin Generation Test (TGT)
timeFrame: Before anticoagulation administration; 5 minutes after anticoagulation; at ≥500 mL blood loss with ongoing bleeding "wet surgical field"; 5 minutes after NovoSeven (activated FVIIa); at end of surgery before ECMO explantation; upon ICU admission
measure: Coagulation Profile Assessed by Standard Laboratory Tests
timeFrame: Before anticoagulation administration; 5 minutes after anticoagulation; at ≥500 mL blood loss with ongoing bleeding "wet surgical field"; 5 minutes after NovoSeven (activated FVIIa); at end of surgery before ECMO explantation; upon ICU admission
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: University Hospital Motol, 2nd Faculty of Medicine, Charles University in Prague and 3rd Department of Surgery, First Faculty of Medicine, Charles University, and Motol University Hospital, Lung Transplant Program
state: Czech Republic
Study officials:
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