PB0582 - Elevated contact pathway activity in patients with acute venous thromboembolism

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Magdolna Nagy, PhD

Postdoctoral Researcher
Coagulation Profile, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands

Co-Author(s)

Alejandro Pallares Robles

PhD student
Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
Mainz, Rheinland-Pfalz, Germany
MV

Mayken Visser

Postdoctoral fellow
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands
Vt

Vincent ten Cate

Postdoc
Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
Mainz, Rheinland-Pfalz, Germany
TK

Thomas Koeck

Head of laboratory
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Mainz, Rheinland-Pfalz, Germany
At

Arina J. ten Cate-Hoek

Associate Professor, MD
Thrombosis Expertise Center, Heart & Vascular Center, Maastricht University Medical Center, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands
Hugo ten Cate, MD, PhD, FAHA

Professor, MD, PhD
Thrombosis Expertise Center, Heart & Vascular Center, Maastricht University Medical Center, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands
PS

Philipp S. S. Wild

Professor
Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
Mainz, Rheinland-Pfalz, Germany
HS

Henri M.H. Spronk

Chief Executive Officer
Coagulation Profile, Maastricht, the Netherlands
Maastricht, Limburg, Netherlands

Background: Venous thromboembolism (VTE) is associated with excessive coagulation activity, which in part can be attributed to activation of the contact system. However, there is limited knowledge on the extent of contact activation in the setting of acute VTE.

Aims: To investigate the impact of contact activation in acute VTE.

Methods: Plasma samples were collected from patients with confirmed acute VTE (n=321;VTEval study) and from population controls without history of VTE (n=300;PREVENT-it pilot study). Both studies were approved by the local ethics committee and Informed consent was obtained for all subjects. Patients were followed for 2 years for the primary endpoint (death or recurrent VTE). FXI levels, FXIa and plasma kallikrein (PKa) activity were determined in plasma samples with an aPTT- or thrombin generation-based assay (FXI:c and CAT:FXIa, respectively) and with ELISA for enzyme-inhibitor complexes (FXIa:alpha-1 antitrypsin(a1AT), FXIa:antithrombin(AT), FXIa:C1-inhibitor(C1-inh), PKa:C1-inh).

Results: VTE patients were slightly older, more often had a history of VTE and antithrombotic agent use compared to controls (Table 1). In VTE patients, higher FXI:c levels (124±37% vs. 114±28%), but lower CAT:FXIa levels were seen. This was accompanied by increased FXIa:a1AT, FXIa:AT and PKa:C1-inh levels in patients compared with controls (312pM [238-424] vs. 203pM [144-288]; 29pM [23-38] vs. 23pM [20-30]; 1.9 nM [1.2-4.7] vs 1.4nM [0.7-3.5], respectively). In contrast, FXIa:C1inh levels were similar in both cohorts (84pM [84-151] vs 84pM [84-103]). Logistic regression models showed good discriminatory value for FXI:c and FXIa:a1AT (AUC=0.64 [0.6/0.69] and AUC=0.73 [0.69/0.77], respectively). After a 2-year follow-up, 81 recurrent VTE events or deaths occurred in the patient cohort, which were predicted by baseline levels of FXIa:a1AT and FXIa:C1Inh (Figure 1.)

Conclusion(s): Elevated FXIa levels and activity are associated with acute and recurrent VTE suggesting an important risk contribution of FXI activation to VTE. These findings support studies with novel FXI(a) inhibitors for prevention of recurrent VTE.