Endogenous Thrombin Potential (ETP) in Patients with Hereditary Antithrombin (AT) Deficiency or Carriers of the Prothrombin (PT) 20210A Gene Mutation.
Authors: Conard Jacqueline , Soustelle Nicolas , Plouy Laura , Horellou Marie-Helene , Samama Meyer-Michel 
Published: October 2019

Hereditary thrombophilias are associated with an increased risk of venous thromboembolism (VTE) but the magnitude of the risk is not the same: very high in AT deficiency type I or type II RS (Reactive Site) or PE (Pleiotropic Effect), moderate or nul in HBS (Heparin Binding Site) type AT deficiency. According to Butenas S, van’t Veer C, Mann KG. (Blood1999; 94: 2169–78), the dominant factors influencing thrombin generation in a synthetic ‘plasma’ system are prothrombin and AT. Determination of the Endogenous Thrombin Potential (ETP) has been proposed as a valuable tool to detect thrombin generation and hypercoagulability.

Aim of the study: Evaluation of ETP in AT deficient patients with different types of deficiency (type I or II) and in carriers of the prothrombin (PT) 20210A gene mutation.

Methods The study concerns 35 AT deficient patients: type I or II RS or PE (n=28) or type II HBS (n=7) and 38 carriers of the PT 20210A mutation (24 heterozygous, 14 homozygous). Patients had no antithrombotic or hormonal treatment and women were not pregnant. They have been compared to 59 healthy subjects. ETP was measured in citrated frozen platelet poor plasma by Hemker method initiated by addition of diluted recombinant tissue factor and phospholipids. The following parameters were recorded: ETP (nM/min) as total Thrombin Generation, Peak (nM) as amount of thrombin generated, Start-to-Tail (ST) minus Time-to-Peak (TTP) (min) as an index of thrombin inhibition. Complete thrombophilia screening was also performed.

Results: ETP is significantly increased in type I or type II RS or PE AT deficient patients and in patients with heterozygous or homozygous PT 20210A mutations as compared to controls (p<.001), but less increased in HBS type II AT deficiency.

n ETP (nM/min) Peak (nM) ST-TTP (min) Controls 59 1484+/−309 296+/−45 15.2+/−1.9 AT HBS 7 1734+/−172 341+/−43 15.2+/−1.1 PT heterozygous 24 2221+/−391 373+/−57 18.3+/−2.7 PT homozygous 14 2606+/−474 385+/−59 21.4+/−3.8 AT I or II RS or PE 28 2655+/−391 359+/−41 25.4+/−5.1

These results demonstrate that ETP, marker of hypercoagulability, is gradually increased in patients with HBS type II AT deficiency, heterozygous and homozygous PT 20210A mutation and in types of AT deficiency other than HBS. The parameter ST-TTP is normal in HBS type II AT deficiency. It reflects the speed of inhibition of the thrombin generated, depending on the amount of thrombin generated and the degree of inhibition.

Conclusion: Our findings suggest that ETP might be useful as a first line test for thrombophilia screening to detect hypercoagulability and ST-TTP as a marker of thrombin inhibition. Results of this large series of patients with AT deficiency and homozygous PT 20210A mutation should be compared with the magnitude of the risk of VTE in different thrombophilias, including patients with factor V Leiden mutation or combined thrombophilias.