Acquired Von Willebrand Disease
Conditions
Brief summary
During treatments with extracorporeal circuits such as extracorporeal membrane oxygenation (ECMO) degradation of high molecular weight (HMW) of von Willebrand factor (vWF) multimers occur leading to an acquired von Willebrand disease. This disease is associated with increased bleeding and requirement for the transfusion with allogenic blood products especially packed red blood cells (PRBCs). A continuous treatment with von Willebrand factor concentrate (vWFC) may restore the multimers and bleeding can be avoided. Therefore a randomized, double-blind, prospective, controlled, two-arm clinical trial was designed, comparing patients receiving vWFC versus placebo.
Detailed description
Increased shear stress during mechanical circulatory support (MCS) by extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VAD) can provoke premature degradation of high molecular weight (HMW) of von Willebrand factor (vWF) multimers. In patients with intractable cardiac and/or respiratory failure requiring emergency ECMO support, the investigators recently demonstrated an essential decrease in high molecular weight (HMW) vWF multimer bands 24 and 48 hours after initiation of ECMO compared to baseline. Blood loss and transfusion requirement during and shortly after ECMO support may be strengthened by loss of HMW vWF multimers. Administration of vWF concentrates may support restoration of primary hemostasis in patients during ECMO support. Consequently the need for packed red blood cells (PRBCs) during ECMO support may be reduced thus positively influencing morbidity and mortality of ECMO patients. The investigators hypothesize, that treatment with vWF concentrate reduces the need for PRBCs during ECMO support. Therefore the primary aim of this clinical trial is to find out if the need of PRBCs differs in the group receiving a von Willebrand factor concentrate (vWFC), or the placebo group (saline). This clinical trial is planned as a randomized, double-blind, prospective, controlled, two-arm, two-center study. Patients with intractable cardiac and/or respiratory failure requiring emergency ECMO support undergoing surgery (Department of Anaesthesiology and Intensive Care Medicine) or treated at the General and Surgical Intensive Care Unit (ACI), Traumatologic Intensive Care Unit (TICU), Cardiologic Intensive Care Unit (CCU) or the ICU of the Department of Visceral, Transplant and Thoracic Surgery at the Hospital Innsbruck (Tirol Kliniken GmbH), Austria will be enrolled in the study when meeting the inclusion- and exclusion criteria. If a patient meets the inclusion criteria and is recruited for the study, the patient will be randomized either to the group receiving vWFC or placebo S. Before the implementation of the ECMO the Baseline investigations need to be conducted. As soon as they are completed the ECMO cannula can be inserted. The administration of the Investigational Medicinal Product (IMP) will be start within 24h after ECMO installation. Directly before IMP-start blood samples (Visit 2) will be drawn. After 24h (Visit 3), 60h (Visit 4) and on day 5 (Visit 5) of the start of the study medication visits will be conducted, whereas on day 5 (Visit 5) no special laboratory (measurement of HMW vWF) will be analyzed. If ECMO can be terminated, a visit (Visit 6) directly before the stop of the ECMO will be conducted. 36 h after the termination of the ECMO Visit 7 (termination) will be performed. If the ECMO is needed longer than 7 days, the administration of the IMP will be stopped on day 7 and a visit after 36 hours of IMP-stop will be done for safety reasons but without special laboratory. After 30 days an interview will be performed with the treating physician.
Interventions
Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)
DRUGSaline Solution
Bolus and continuous infusion of the Investigational Medicinal Product (IMP) during extracorporeal membrane oxygenation (ECMO)
Sponsors
LFB BIOMEDICAMENTS
Tirol Kiniken GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The vWFC or placebo will be prepared by the local hospital pharmacy or independent nurses from another ward (on holidays and weekends). To keep the blinding for the treating physicians and the study team syringes and lines with light protection (orange color) will be used. So the color of the medication (colorless to slightly yellowish) cannot be distinguished.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with the need of veno-arterial or veno-venous ECMO for a minimum of 48 hours * Age ≥ 18 years
Exclusion criteria
* Patient with known thromboembolic event in the last 30 days * Inevitable lethal course * Severe Liver failure: Quick \< 30 % * Pregnancy * Patient with known refusal of a participation in this clinical trial * Active participation in another clinical trial * Any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she were to participate in the study or confound the ability to interpret data from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Transfusion requirement of PRBC | Between start of IMP (Visit 2) until 24 hours after IMP-start (Visit 3) | Difference in the number of red blood cells concentrates between the treatment arms per day |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Requirements of coagulation factor concentrates | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Amount of coagulation factor concentrates given during ECMO support between the treatment arms per day |
| Number of vWF-HMW multimer bands | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Number of vWF multimer bands measured via SDS-agarose gel electrophoresis between the treatment arms |
| Assessment of thromboelastometry | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Difference in thromboelastometry between the treatment arms |
| Changes in thrombocytes | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Difference in platelet number |
| Renal function | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Difference in the daily urine output |
| Number of participants with bleeding events | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Number of patients with bleeding events assessed by a bleeding score based on Mazzeffi et al 2013 |
| Transfusion requirements of other allogenic blood products | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Difference in the number of other high risk allogenic transfusion products (fresh frozen plasma and platelet concentrate) between the treatment arms per day |
| Assessment of activated partial thromboplastin time (aPTT) assay | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | aPTT assay \[seconds\] between the treatment arms |
| Changes in red blood cell number | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | Differences in red blood cell number and hemoglobin between the treatment arms |
| Number of participants with thromboembolic events | 36 hours after IMP-Stop | Number of participants with thromboembolic events as assessed via duplex ultrasonic investigation of the cervical vessels (Carotis und Vertebralis) and major leg veins |
| Assessment of Prothrombin time (PT) assay | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | PT assay \[%\] between the treatment arms |
| Assessment of activated clotting time (ACT) | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | ACT assay \[seconds\] between the treatment arms |
| Assessment vWF-HMW function | Between start of ECMO (Visit 1) and 36 hours after ECMO Stop (Visit 7) | vWF function (vWF:Ag, vWF:RCo, and F:VIII) via photooptical measurement between the treatment arms |
Countries
Austria
Outcome results
None listed