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Coenraad H. Hemker
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Bleeding, Thrombosis and Vascular Biology
Endogenous thrombin potential
The clinical usefulness of measuring thrombin generation
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Invited Editorials
2023-03-06
2023-01-30
2023-01-27
2023-04-04
Bleed Thromb Vascul Biol
Coenraad H. Hemker
2023/03/06
10.4081/btvb.2023.62
Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research Institute of Maastricht, Maastricht University Medical Centre, Maastricht
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Endogenous thrombin potential
en
Dyer O. Bayer and Janssen pay $775 m to settle Xarelto misinformation claims. BMJ 2019; 364:I1413.
The clinical usefulness of measuring thrombin generation
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                                                                                                          INVITED EDITORIAL

The clinical usefulness of measuring thrombin generation
H. Coenraad Hemker

Laboratory for Clinical Thrombosis and Haemostasis, Departments of Internal Medicine and Biochemistry, Cardiovascular Research
Institute of Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands




    In medicine there are hardly any universally valid                       tential (ETP) and it is represented by the surface under the
rules, but the first law of hemostasis and thrombosis might                  thrombin generation curve.1
be among the exceptions: The more thrombin the less                               Thrombosis and bleeding bring an inestimable burden
bleeding but the more thrombosis; the less thrombin the                      of death and disease. The exact numbers are impossible
more bleeding, but the less thrombosis.                                      to assess because thrombosis, as Nobody’s disease but
    What is loosely called thrombin here is the amount of                    everybody’s complication [Lord Ajay Kakkar dixit] does
enzymatic work that thrombin potentially can do in the                       not, as such, appear in the mortality statistics. A rough es-




                                                                                               ly
time between its generation and its disappearance in a clot                  timate attributes around half of all causes of death in Eu-




                                                                                       on
or thrombus. We called it the Endogenous Thrombin Po-                        rope to thrombosis (Table 1).2
                                                                                  The mortality due to bleeding-by-lack-of-thrombin is
                                                                             even more difficult to estimate; the severity of a bleeding




                                                                                 e
                                                                             being determined by the extent of the wound and the ad-
  Correspondence: H. Coenraad Hemker, Laboratory for Clinical
  Thrombosis and Haemostasis, Departments of Internal Medicine
                                                                            us
                                                                             equacy of the hemostatic reaction. The impressive figures
                                                                             on bleeding due to over-anticoagulation that we will en-
  and Biochemistry, Cardiovascular Research Institute of Maastricht,         counter below set a lower limit.
                                                                            al
  Maastricht University Medical Centre, Maastricht, the Netherlands.              Nobody will deny that being able to gauge the mech-
  E-mail: coen@hemker.nl
                                                         ci

                                                                             anism behind so much pathology is a major asset. For cen-
  Citation: Hemker HC. The clinical usefulness of measuring thrombin         turies we had to deal with clotting times. They are good
                                                       er


  generation. Bleeding, Thrombosis, and Vascular Biology 2023;2:62.          to explore severe hypocoagulability but fail in hyperco-
                                                                             agulability and in modest hypocoagulability. The reason
                                                      m



  Key words: Thrombin, Endogenous thrombin potential.
                                                                             is that a clotting time is inversely related to the amount of
                                          om




  Conflict of interest: The author declares no potential conflict of in-     thrombin formed so that, grosso modo, the whole spec-
  terest.                                                                    trum of ETP values >50% of normal is represented by
                                                                             clotting times that are less than twice prolonged.
                                    -c




  Funding: None.
                                                                                  The superiority of the ETP as a function test is well il-
                                                                             lustrated in the specialised field of hemophilia. It is well
                           on




  Availability of data and material: The data used to support the find-
  ings of this study are available from the corresponding author upon        known that severe and moderate bleeding is only loosely
  request.
                                                                             related to the native factor VIII level, let alone to a clotting
                     N




  Informed consent: The manuscript does not contain any personal             time in any of its variations. There is, however, a perfect
  data in any form.                                                          correlation of the native ETP with clinical severity.2 The
                                                                             adequacy of substitution therapy as well as of alternatives,
  Received for publication: 30 January 2023.
  Accepted for publication: 7 February 2023.                                 such as bypass with other (activated) clotting factors,
                                                                             downregulation of antithrombin, factor VIII replacing an-
  Publisher’s note: All claims expressed in this article are solely those    tibodies etc. can also be judged by the ETP and not by
  of the authors and do not necessarily represent those of their affili-     clotting times or factor VIII tests. It therefore is a useful
  ated organizations, or those of the publisher, the editors and the re-
  viewers. Any product that may be evaluated in this article or claim
                                                                             guide during surgical interventions in hemophiliacs with
  that may be made by its manufacturer is not guaranteed or endorsed         inhibitors.3
  by the publisher.                                                               Another, and much more common use of the ETP is
                                                                             in parenchymatous liver disease, where the synthesis of
  ©
   Copyright: the Author(s), 2023
                                                                             plasma proteins is impaired. The prothrombin time then
  Licensee PAGEPress, Italy
  Bleeding, Thrombosis and Vascular Biology 2023; 2:62                       is usually prolonged, but the ETP will be hardly dimin-
  doi:10.4081/btvb.2023.62                                                   ished – if at all. This is because the anticoagulant proteins
                                                                             – antithrombin e.g. – are decreased to the same extent as
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).
                                                                             the clotting factors are, but have no influence on the pro-
                                                                             thrombin time. According to some protocols procoagulant

                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:62
24                                                               C.H. Hemker




treatment is given to cure the prothrombin time, which in-                   In real life the distribution curve of the treated popu-
creased the risk of thrombosis as an immediate result.4                  lation will be still broader because this in vitro experiment
    By far the most common disturbance of the clotting                   only reflects the pharmacodynamic response, the direct
system is iatrogenic, viz. prophylaxis of thrombosis. All                influence of the drug on its target, and variation due to
anticoagulant treatment amounts to decreasing thrombin                   variability in uptake and clearance are not considered.
generation capacity, either by decreasing procoagulant                   Also, the distribution curve will be shifted to the right be-
factors - vitamin K antagonists (AVK) or direct oral anti-               cause patients under anticoagulant treatment will not be
coagulants (DOACs) - increasing antithrombin activity                    a random representation of the normal population, like in
(heparins) or direct inhibition (DOACs).                                 Figure 1, because the higher quartiles of the normal pop-
    In the normal population the between-person variation                ulation, with their larger risk of thrombosis, will be over-
is high.5 In the highest quartile the relative risk of venous            represented.
thrombosis (RRVT) is seven times as high as in the low-                      From these experiments one may surmise that admin-
est.6 In non-O blood groups the ETP is 108% and the                      istration of a standard dose of DOAC causes a highly vari-
RRVT 2.2, in the blood group O it is 92% and 0.7.7 In an-                able response of the ETP in a population of patients, so
other study the risk is 0.57 in the group with a below av-               that only a fraction of it will be optimally anticoagulated.
erage and 2.2 in the group with an above average ETP.8                   This, by the way, has also been found for two other




                                                                                                    ly
So in the broad range of normal ETPs there is a strong                   DOACs, for heparin and for heparin likes.12




                                                                                            on
variation of thrombotic risk between the higher and the                      Now any decrease of the ETP, optimal or not, will
lower ones.                                                              bring about an important attenuation of the risk of throm-
    In studies on bleeding in orally anticoagulated popu-                bosis. A person that normally has an ETP of 120% of nor-




                                                                                      e
lations and in patients with congenital deficiencies of clot-            mal may, even if he/she is a bad responder to a DOAC,
ting factors it has been found that the risk of bleeding
hardly increases unless the ETP falls below of 30% of nor-
                                                                               us
                                                                         attain an ETP of 75% and thus reduce his/her relative risk
                                                                         from 2 to 0.6, thus contributing significantly to the favor-
                                                                         able statistics in the treated group. Nevertheless, much is
mal.9,10 In patients on an INR of 2-3, corresponding to an
                                                                        al
ETP of ~ 40±6%, the RRVT is ~0.2.10                                      to be gained if the dosage would be individualised so as
                                                                         to be maintained in the 35-65% zone.
                                                            ci

    It follows that stable anticoagulation to an ETP of
                                                                             Why is this not envisaged for the moment?
about 35-65% of normal (Figure 1) will keep a population
                                                          er


                                                                             The first and foremost reason is that before the advent
on a minimal risk of thrombosis with a hardly increased
                                                                         of thrombin generation measurement, it was not possible
                                                         m



risk of bleeding.
    The modern DOACs open promising horizons to
                                                 om




achieve this. Clinical trials have shown that, given in stan-
dard doses they protect slightly better than vitamin K an-
tagonists do. Recent studies have shown that there are
                                         -c




obviously good and bad responders to the drug: a fixed
                                   on




concentration of 300 nM rivaroxaban inhibits the ETP in
normal persons by 45±10.6%.11 Such variations superim-
pose upon the considerable interindividual variation to re-
                            N




sult in a very broad distribution of ETP after inhibition
and that only partly lies in the ideal zone (Figure 1).




Table 1. Death in Europe per 100,000 inhabitants (2017).
                           Total      Thrombosis            %
Coronary infarction         277            277             100
Stroke                      189            151              80
Cancer                      304            101              33
Miscellaneous               283            >35             >12
Total                      1053           >564             >53           Figure 1. Distribution of the endogenous thrombin potential
                                     Source: Eurostat (ec.europe.eu).    before and after inhibition with a direct oral anticoagulant. White
Miscellaneous: e.g. pulmonary and other embolisms, diffuse               dots: Normal volunteers (N>7000). Black dots: Same plasmas
intravascular micro-embolization. If thrombosis due to cancer is not     in the presence of IC50 of a DOAC. Gray zone: Zone of optimal
counted the total % drops to >44.                                        anticoagulation.


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:62
                                     The clinical usefulness of measuring thrombin generation                                       25



to adequately measure the effect of DOACs on the clot-
ting system. When the trials on DOACs were planned,                 REFERENCES
thrombin generation measurement was only known as a                  1. Hemker HC, Béguin S. Thrombin generation in plasma: its
research tool and no reliable laboratory automaton was as               assessment via the endogenous thrombin potential. Thromb
yet available for its large-scale application.                          Haemos 1995;74:134-8.
     A second reason is that discarding laboratory control           2. Dargaud Y, Negrier C, Rusen L, et al. Individual thrombin
                                                                        generation and spontaneous bleeding rate during personal-
is a tremendous advantage over anti-vitamin K treatment
                                                                        ized prophylaxis with Nuwiq®(human-cl rh FVIII) in pre-
sparing both money and hassle. It thus compensates in                   viously treated patients with severe haemophilia A.
part for the much higher costs of DOACs over AVK and                    Haemophilia 2018;24:619-27.
is an important selling argument, not ready to be dropped            3. Dargaud Y, Lienhart A, Janbain M, et al. Use of thrombin
by pharmaceutical firms.                                                generation assay to personalize treatment of breakthrough
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treatment is not what would be needed, rather dose ad-                  prophylaxis with emicizumab. Haematologica 2018;103:
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justment, is used, like blood-pressure to tailor antihyper-
                                                                     4. Lebreton A, Sinegre T, Lecompte T, et al. Thrombin gener-
tensive drugs and blood sugar that of antidiabetics.                    ation and cirrhosis: state of the art and perspectives. InSem-
     There is another reason to consider dose adjustment.               inars in thrombosis and hemostasis 2020;46:693-703.




                                                                                      ly
Bleeding due to overdosage of DOAC is not a rare occur-              5. Bloemen S, Huskens D, Konings J, et al. Interindividual




                                                                              on
rence. The incidence is ~3 per 100 patient-years.13 That                variability and normal ranges of whole blood and plasma
makes 100.000 bleeds per year on the 3.5 million patients               thrombin generation. J Appl Lab Med 2017;2:150-64.
on DOACs in the United States.14 One might consider                  6. Winckers K, van Hylclama Vlieg A, Thomassen MCLGD,




                                                                         e
spotting over-responders before they start bleeding, be it              et al. Thrombin Generation and the risk of venous thrombo-
                                                                        sis: results from a large population-based case-control study.
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German drug maker Bayer and the Johnson & Johnson
                                                                  us    ISTH Toronto 2015.
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subsidiary Janssen Pharmaceuticals will jointly pay                     variability and normal ranges of whole blood and plasma
                                                            al
$775m (£587m; €687m) to settle more than 25 000 law-                    thrombin generation. J Appl Lab Med 2017;2:150-64.
                                               ci

suits in US federal and state courts, representing almost            8. Hron G, Kollars M, Binder BR, et al. Identification of pa-
all of the outstanding claims against the bestselling anti-             tients at low risk for recurrent venous thromboembolism by
                                             er


coagulant rivaroxaban (Xarelto).15                                      measuring thrombin generation. Jama 2006;296:397-402.
                                                                     9. Al Dieri R, Peyvandi F, Santagostino E, et al. The thrombo-
     If one wants patient-based evidence to see whether
                                            m



                                                                        gram in rare inherited coagulation disorders: its relation to
dose adjustment would pay of, one does not need to start                clinical bleeding. Thromb Haemos 2002;88:576-82.
                                   om




large, costly, and cumbersome trials. It would suffice to           10. Azar AJ, Cannegieter SC, Deckers JW, et al. Optimal inten-
collect samples from a sufficiently large number of bleed-              sity of oral anticoagulant therapy after myocardial infarction.
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                             -c




laxis and see whether their basic ETP will indeed be in             11. Zwaveling S, Bloemen S, Castoldi E, et al. Response of
the low range for those who bleed and high in case of                   thrombin generation to rivaroxaban in twin-families: influ-
                      on




                                                                        ence of sex and contraceptives. Abstract 144150. ISTH con-
thrombosis.
                                                                        gress. Montreal 2023.
     Finally: Above we have preferred to give three exam-
                 N




                                                                    12. Bloemen S, Hemker HC, Al Dieri R. Large inter-individual
ples of the clinical use of thrombin generation. One where              variation of the pharmacodynamic effect of anticoagulant
the use of ETP is recognised and used in actual practice,               drugs on thrombin generation. Haematologica. 2013
i.e. hemophilia; another where it is in the process of being            Apr;98:549.
accepted in the clinic, i.e. in liver disease and one where         13. Eikelboom J, Merli G. Bleeding with direct oral anticoagu-
the future use of thrombin generation would cause a                     lants vs warfarin: clinical experience. Ame J Med 2016;129:
                                                                        S33-40.
tremendous health benefit once it were adopted: DOAC
                                                                    14. Troy A, Anderson TS. National trends in use of and spending
medication.                                                             on oral anticoagulants among US Medicare beneficiaries
     It is likely that in the future, Thrombin Generation will          from 2011 to 2019. InJAMA Health Forum 2021;2:e211693.
ameliorate diagnosis and treatment everywhere where                 15. Dyer O. Bayer and Janssen pay $775 m to settle Xarelto mis-
now clotting times are used.                                            information claims. BMJ 2019; 364:I1413.




                                      Bleeding, Thrombosis and Vascular Biology 2023; 2:62
