Coagulation in Acute Aortic Dissection (CAAD)

Impact of Anticoagulation Management on Thrombin Generation During Surgery for Acute Aortic Dissection

Acute aortic dissection (AAD) involving the ascending aorta (Stanford classification type A) remains a life-threatening disease. Excessive perioperative bleeding requiring massive transfusion of allogeneic blood products, and surgical reexploration remain major challenges in these patients. Previous research has indicated that patients with AAD show pronounced haemostatic alterations prior to surgery which are aggravated during major aortic surgery with cardiopulmonary bypass and hypothermia full heparinization.

Intensified anticoagulation management guided by heparin dose response (HDR) calculation, and repeated measurement of heparin concentration may be more effective than standard empiric weight-based heparin and protamine management monitored by activated clotting time (ACT) measurements to suppress thrombin generation during surgery for AAD.

This randomized controlled clinical trial compares the impact of two recommended anticoagulation management strategies during surgery for AAD including deep hypothermia on activation of coagulation: Heparin/protamine-management based on HDR-titration by means of HMS Plus® versus current institutional standard (HDR- versus ACT-approach).

Primary endpoint is thrombin generation as measured by early postoperative prothrombin fragment 1+2 (F1+2). Secondary endpoints are other markers of coagulation and fibrinolysis as well as clinical outcome.

Study Overview

• Status: Completed
• Conditions: Coagulation Disorder; Acute Aortic Dissection
• Intervention / Treatment: Procedure: Individualized HDR-approach; Procedure: Conventional ACT-approach

Detailed Description

Hypotheses:

Primary: HDR-approach is superior to ACT-approach in terms of suppressing thrombin generation after emergent surgery for acute aortic dissection (Stanford type A).

Secondary: HDR-approach is superior with regard to

• early postoperative haemostatic capacity
• requirement of blood product transfusion and haemostatic agents
• postoperative bleeding

Design:

Investigator-initiated, single-site, parallel-group (1:1), prospective, randomized, partially double-blinded trial in patients undergoing emergent surgery for acute aortic dissection comparing two heparin management strategies with superiority design. Prior to randomization, patients are stratified according to preoperative organ dysfunction and anticoagulation therapy.

Acute research study design as patients with acute aortic dissection are considered incompetent according to the Danish Research Ethics Committees definition. Deferred consent by the competent patient or her/his proxy (next of kin) and an independent physician) is used. 26 consecutive patients undergoing emergent surgery for acute aortic dissection (Stanford type A) are randomized 1:1 into the following heparin management strategies with an ACT target of 480 seconds:

• Individualised HDR-approach
• Conventional ACT-approach

No interim analysis. A sub-study to compare cost-benefit of both strategies is planned.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus University Hospital Skejby

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age > 18 years
• Emergent Acute Aortic Dissection with cardiopulmonary bypass
• Incapable of providing informed consent

Exclusion Criteria:

• History of congenital coagulation disorder (haemophilia)
• Previous open cardiac surgery
• Death during induction of anaesthesia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Individualised HDR-approach; HMS Plus® Hemostasis Management System (Medtronic International, Tolochenaz, CH).	Procedure: Individualized HDR-approach; Heparin concentration necessary to achieve target ACT > 480 sec. calculated based on individual HDR-curve. If HDR slope ˂80 s/IU/mL (reduced sensitivity to heparin), 1000 IU of AT concentrate (Antitrombin III "Baxalta"®, Takeda Pharma, Vallensbæk Strand, DK). Whole blood concentration of circulating heparin assessed by heparin assays. Additional heparin given as required. After weaning, protamine necessary to reverse circulating heparin calculated according to heparin-protamine titration measurement. After protamine, heparin reversal evaluated with low-range heparin-protamine titration cartridge and additional protamine given as required.
Active Comparator: Conventional ACT-approach; ACT Hemostasis Management	Procedure: Conventional ACT-approach; Initial Heparin 400 IU/kg (500 IU/kg if treated with heparin prior to surgery). ACT Assessment with Hemochron® Signature Elite (ITC, International Technidyne Corp., Edison, NJ, USA). Additional heparin until ACT > 480 sec. If ACT < 480 sec. after despite repeated heparin supplement with 1000 IU of AT III concentrate. Target ACT > 480 sec. during normothermic CPB, and target ACT > 700 seconds during hypothermia After weaning, protamine 10mg/mL (0.7 mg of protamine/ 100 IU total heparin administered). Heparin reversal is evaluated with an activated partial thromboplastin (APTT). If APTT > 40 seconds, additional protamine (25-50 mg i.v.).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
F1+2	Prothrombin fragment 1+2 (pmol/L)	up to 2 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TAT	Thrombin-Antithrombin Complex (ug/L)	up to 2 days after surgery
ETP	Endogenous Thrombin Potential (nmol/L x min)	up to 2 days after surgery
Thrombin time	High-dose thrombin time (sec)	up to 2 days after surgery
Antithrombin	(kIU/L)	up to 2 days after surgery
D-dimer	D-dimer (mg/L)	up to 2 days after surgery
Clot lysis	Clot lysis	up to 2 days after surgery
Heparin sensitivity	Heparin sensitivity (slope)	prior to surgery
Heparin (total)	Total amount of heparin	immediately after surgery
Protamin (total)	Total amount of protamin	immediately after surgery
Ratio	Protamin/heparin ratio	immediately after surgery
Resistance	Heparin resistance	immediately after surgery
Blood cell-saver	Volume of blood processed in cell-saver (mL)	immediately after surgery
Blood loss sponges	Gravimetric estimation of intraoperative blood loss (calculation based on the change between dry and blood-soaked sponges, accounting for irrigation) in mL	immediately after surgery
Drain output	Total mediastinal drain output (ml)	48 hours after surgery
Blood tranfusion	Tranfusion of blood products (units): Red blood cells, fresh frozen plasma, platelet concentrates	48 hours after surgery
Fibrinogen	Administration of fibrinogen concentrate (mg)	24 hours after surgery
PCC	Administration of prothrombin complex concentrate (Octaplex) (IU)	24 hours after surgery
AT concentrate	Administration of Antithrombin concentrate (IU)	24 hours after surgery
Cryoprecipitate Plasma	Administration of cryoprecipitate plasma	24 hours after surgery
Recombinant FVIIa	Administration of Recombinant FVIIa	24 hours after surgery
2. Closure	Secondary closure	30 days after surgery
Reoperation for bleeding	Reexploration for bleeding (yes/no)	30 days after surgery
Protocol violation	Protocol violation (yes/no)	immediately after surgery
Mortality	All-cause mortality	up to 90 days after surgery
Stroke	Stroke (yes/no)	30 days after surgery
Myocardial infarction	Perioperative myocardial infarction (yes/no)	30 days after surgery
Renal	Requirement of continuous renal replacement therapy (yes/no)	30 days after surgery
Low cardiac output syndrome	Low cardiac output syndrome requiring inotropics or mechanical support (yes/no)	30 days after surgery
Vascular malperfusion	Visceral og peripheral vascular malperfusion requiring surgical or percutaneous intervention	30 days after surgery
Intraop. coagulation	Clinical signs of coagulation during CPB (yes/no)	Immediately after surgery
Length of surgery	minutes	30 days after surgery
Length of stay ICU	days	30 days after surgery
Length of hospitalization	Hospitalization (days)	30 days after surgery

Collaborators and Investigators

• Sponsor: Ivy susanne Modrau, MD
• Investigators: Principal Investigator: Jens Eschen, Stud.med., Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Denmark; Study Chair: Ivy Modrau, MD, dr.med., University of Aarhus

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Actual): September 17, 2024
• Study Completion (Actual): December 15, 2024

Study Registration Dates

• First Submitted: May 26, 2022
• First Submitted That Met QC Criteria: July 30, 2022
• First Posted (Actual): August 2, 2022

Study Record Updates

• Last Update Posted (Actual): July 18, 2025
• Last Update Submitted That Met QC Criteria: July 15, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Dissection, Blood Vessel; Acute Aortic Syndrome; Vascular Diseases; Cardiovascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Aortic Diseases; Aneurysm; Aortic Dissection; Hemostatic Disorders; Blood Coagulation Disorders
• Other Study ID Numbers: 1-10-72-30-22

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
• product manufactured in and exported from the U.S.: No