Comparison of Biocompatibility of Plasmapheresis Procedures With Citrate and Heparin Anticoagulation

Membrane plasmapheresis is one of the methods for treating immune diseases. Plasmapheresis removes autoantibodies and immune complexes, paraproteins, lipoproteins and reduces the concentration of cytokines. In membrane plasmapheresis, plasma is separated from blood cells by a highly permeable membrane. The filtered plasma is then discarded and replaced with replacement fluid. During the procedure, there is an activation of the coagulation system, because of the extracorporeal blood circulation. The anticoagulation during the procedure is therefore necessary.

Study Overview

• Status: Completed
• Conditions: Anticoagulation; Apheresis
• Intervention / Treatment: Drug: unfractionated heparin; Drug: Sodium Citrate

Detailed Description

Standard heparin or citrate is routinely used as a method of anticoagulation in plasmapheresis. Citrate provides effective anticoagulation that is completely limited to extracorporeal circulation. Patients who are at increased risk for bleeding, anticoagulation with citrate is a more appropriate method than standard heparin, while in other patients both methods are equivalent.

Citrate anticoagulation is performed by infusing citrate into the arterial line of the extracorporeal system. Citrate binds to plasma calcium and thus inhibits coagulation in the system. Calcium is added to the venous line of the system (when blood returns to the patient) to maintain a normal plasma ionized calcium concentration. Lowering the ionized calcium in the blood in the extracorporeal circulation inhibits the coagulation and activation of other systems (platelets, leukocytes, complement), which affects the biocompatibility of the artificial material and the whole procedure. Biocompatibility is extremely important, since the contact of blood with artificial material activates both the humoral and cellular systems. As part of the humoral immune system, complement is activated by the production of C3, C4 and C5, factor XIIa, there is also an increase in the production of bradykinin, kallikrein, quinine and plasmin, and some proteins are denatured (gamma globulins, fibrinogen, albumins). When the cellular immune system is activated, lymphocytosis can occur and the is also change in function of phagocytes.

All previous studies show that regional anticoagulation with citrate improves biocompatibility in hemodialysis procedures (compared to heparin anticoagulation), but no direct comparison in plasmapheresis has been observed in the literature so far.

Therefore, the investigators want to conduct a prospective randomized study comparing several parameters of heparin and citrate anticoagulation biocompatibility during plasmapheresis. The aim of the study is to demonstrate better biocompatibility in citrate anticoagulation compared to heparin.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 4

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1210
    • University Medical Center Ljubljana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• older than 18 years
• an indication for plasma exchange (plasmapheresis) with albumin solution as a replacement solution

Exclusion Criteria:

• contraindication for systemic heparinisation
• acute bleeding
• known active malignancy
• severe infection
• anticoagulant therapy at therapeutic dose

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: heparin anticoagulation; standard heparin anticoagulation during plasmapheresis	Drug: unfractionated heparin; standard heparin at 2500 IU i.v. bolus and then 2000 IU/h continuously i.v. for anticoagulation during plasmapheresis
Experimental: citrate anticoagulation; sodium citrate anticoagulation during plasmapheresis	Drug: Sodium Citrate; 8% sodium citrate at approx. 27 mmol/h i.v. for anticoagulation during plasmapheresis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in serum thrombin-antithrombin complex from baseline to 30 minutes	thrombin-antithrombin complex	30 minutes after start of plasmapheresis
change in serum thrombin-antithrombin complex from baseline to the end of plasmapheresis	thrombin-antithrombin complex	at the end of plasmapheresis procedure
change in serum platelet factor 4 from baseline to 30 minutes	platelet factor 4	30 minutes after start of plasmapheresis
change in serum platelet factor 4 from baseline to the end of plasmapheresis	platelet factor 4	at the end of plasmapheresis procedure
change in serum C5a from baseline to 30 minutes	complement component C5a	30 minutes after start of plasmapheresis
change in serum C5a from baseline to the end of plasmapheresis	complement component C5a	at the end of plasmapheresis procedure
change in serum myeloperoxidase from baseline to 30 minutes	myeloperoxidase	30 minutes after start of plasmapheresis
change in serum myeloperoxidase from baseline to the end of plasmapheresis	myeloperoxidase	at the end of plasmapheresis procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
complications during plasmapheresis (hypocalcemia, metabolic alkalosis, clotting)	complications during plasmapheresis (hypocalcemia, metabolic alkalosis, clotting)	during plasmapheresis
comparison of measured platelet factor 4 in patients' serum and filtered plasma	A Bland-Altman agreement analysis	30 minutes after start of plasmapheresis
comparison of measured thrombin-antithrombin complex in patients' serum and filtered plasma	A Bland-Altman agreement analysis	30 minutes after start of plasmapheresis
comparison of measured C5a in patients' serum and filtered plasma	A Bland-Altman agreement analysis	30 minutes after start of plasmapheresis
comparison of measured myeloperoxidase in patients' serum and filtered plasma	A Bland-Altman agreement analysis	30 minutes after start of plasmapheresis

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2022
• Primary Completion (Actual): December 30, 2022
• Study Completion (Actual): December 30, 2022

Study Registration Dates

• First Submitted: December 12, 2021
• First Submitted That Met QC Criteria: December 29, 2021
• First Posted (Actual): January 13, 2022

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Chelating Agents; Sequestering Agents; Calcium Chelating Agents; Heparin; Calcium heparin; Citric Acid; Sodium Citrate
• Other Study ID Numbers: 0120-310/2017/3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No