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Kallikrein Augments the Anticoagulant Function of Protein C System in Thrombin Generation

1Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, Netherlands, 2Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands, 3Department for Genomics & Immunoregulation, Life and Medical Sciences 12 Institute (LIMES), University of Bonn, Bonn, Germany, 4Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands

Abstract Number: OC 27.2

Meeting: ISTH 2021 Congress

Theme: Coagulation and Natural Anticoagulants » Protein C Pathway

Background: The protein C pathway is a major regulator of thrombin generation (TG). Activated protein C (APC)-resistance is a well-established risk for thrombosis.

Aims: We aimed to explore the whole genome of approximately 500 healthy volunteers on genetic determinants of thrombin generation (TG) and thrombomodulin-modulated TG.

Methods: Platelet poor plasma (PPP) of approximately 500 healthy individuals of Western-European background from the Human Functional Genomics Project was used, with approval from local Ethical Committee and written informed consent from the participants. TG was measured with the Calibrated Automated Thrombography (CAT) assay after triggering with 5 pM tissue factor. In parallel, we performed, in each plasma sample, an identical CAT assay in the presence of thrombomodulin to assess the function of the protein C pathway. Genetic determinants of TG parameters and protein C pathway function were assessed using genome-wide single-nucleotide polymorphism (SNP) genotyping. Purified human kallikrein was supplemented to normal pooled plasma to verify its effect on TG modified with thrombomodulin and APC.

Results: TG data from 434 individuals were analyzed and genotyping showed that several loci on chromosome 4 on the KLKB1 gene (top SNP ID: rs4241819) were linked to the inhibitory capacity of thrombomodulin on endogenous thrombin potential (nETP_TMsr, p = 4.27 x 10-8) (Figure 1). In vitro supplementation of kallikrein into normal pooled plasma dose dependently augmented the anticoagulant effect of thrombomodulin and APC in TG, and 120 nM kallikrein resulted in over 30% stronger inhibition of thrombin formation by thrombomodulin or APC (Figure 2).

Figure 1. Genome-wide significant loci associated with protein C pathway function (normalized sensitivity ratio of endogenous thrombin potential to thrombomodulin; nETP_TMsr).Figure 2. Effect of kallikrein (PKa) supplementation on the anticoagulant effect of thrombomodulin (TM) / activated protein C (APC) on TG.

Conclusions: Our results suggest that kallikrein plays a role in the regulation of the anticoagulant protein C pathway in TG.

To cite this abstract in AMA style:

Wan J, Vadaq N, Konings J, G Netea M, de Laat B, J van der Ven A, Joosten L, Jaeger M, Kumar V, G de Groot P, de Mast Q, Roest M. Kallikrein Augments the Anticoagulant Function of Protein C System in Thrombin Generation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/kallikrein-augments-the-anticoagulant-function-of-protein-c-system-in-thrombin-generation/. Accessed October 1, 2023.

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