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Editorials
type in subjects with hemophilia12 or other rare congenital diseases.13
Monitoring treatment with pro-hemostatic agents
In principle, every treatment aimed at preventing/treat- ing hemorrhage accomplishes its goal by increasing thrombin generation. In this respect, the TG procedure is the most promising laboratory tool to monitor patients on treatment. As an example, TG has been used in hemo- philia with inhibitors to factor VIII or IX to tailor treat- ment with conventional bypassing agents.14 These drugs achieve their hemostatic effect with no substantial modi- fication of factors VIII/IX, thus making the measurement of these factors after infusion practically useless. However, the studies carried out so far, while providing evidence that TG is increased according to the dose of the drug infused to treat/prevent hemorrhage, failed to pro- vide conclusive evidence that the laboratory endpoint is associated with clinical outcomes.15 Therefore, the proce- dure is not yet approved by the regulatory authorities for routine use in hemophilia patients being treated with bypassing agents.
Monitoring treatment with antithrombotic drugs
There is no doubt that TG is decreased in a dose-depen- dent fashion in patients treated with any antithrombotic drug (e.g., heparins, parenteral direct thrombin inhibitors, warfarin or direct oral anticoagulants). However, there is still no conclusive evidence that the TG procedure is superior for treatment monitoring to the APTT (unfrac- tionated heparin), anti-factor Xa assays (low molecular weight heparin), the PT-International Normalized Ratio (warfarin) or the specific measurement of the plasma con- centration of direct oral anticoagulants.
Predicting the risk of recurrent venous thromboembolism
There is evidence stemming from clinical trials that the amount of thrombin generated after the in-vitro activation of coagulation is a good predictor of the risk of a recur- rence of venous thromboembolism. In this respect, TG should be equivalent (as a risk predictor) to D-dimer,16,17 which, following the seminal observations of Palareti and co-workers,18 is used to make decisions on the optimal duration of anticoagulation to prevent recurrence of venous thromboembolism. Although these studies showed that TG and D-dimer are independently associat- ed with the risk of recurrent venous thromboembolism, there is no conclusive evidence that performing the two measurements simultaneously can improve risk predic- tion in individual patients.18
New observations on thrombin generation
The above observations are instrumental to supporting the old concept that hypercoagulability, when assessed by a global coagulation procedure, is one of the key mechanisms that explain the risk of thrombosis, the oth- ers being reduced blood flow and endothelial dysfunction (collectively known as Virchow triad). In this issue of the Journal van Paridon et al. add more evidence on the mech- anisms of hypercoagulability and clinically relevant out- comes.1 They evaluated TG in a large population of sub- jects (n=5,000) enrolled in a prospective study with a rel-
atively long follow-up (up to 9.65 years). The authors found that some TG parameters were independently associated with overall mortality. In particular, the study showed that the ETP and lag-time were directly associat- ed with overall mortality. Furthermore, these parameters were associated with some conditions (e.g., age, obesity, diabetes, dyslipidemia, use of oral contraceptives or hor- monal replacement therapy) that are known risk factors for cardiovascular disease. The study by van Paridon et al. is the first to investigate the association of hypercoagula- bility (as measured by TG) and the risk of mortality in a large population.1 However, some issues emerge from the study that warrant consideration. While it is plausible that high ETP is directly associated with overall mortality, it is less plausible that the prolonged (not shortened) lag- time is associated with mortality. It should however be recognized that a prolonged lag-time has been hypothe- sized to be associated with increased levels of tissue fac- tor pathway inhibitor, one of the naturally occurring anti- coagulants. Unfortunately, the authors did not provide data on tissue factor pathway inhibitor in their cohort, nor did they report other parameters of TG such as the time to reach the peak concentration. One may wonder whether or not the latter parameter would be more rep- resentative than the lag-time to describe the real situation concerning the velocity of TG, which might help to understand the mechanism of thrombogenesis. Furthermore, the study did not investigate the association between TG and cardiovascular mortality. This would have been a more plausible association between hyperco- agulability and clinical outcome. Notwithstanding these limitations, the study by van Paridon et al. should be con- sidered an important step forward for the development of TG as a global procedure to assess the hemostatic system and its relationship with overall mortality.1
References
1. van Paridon PCS, Panova-Noeva M, van Oerle R, et al. Thrombin generation in cardiovascular disease and mortality - results from the Gutenberg Health Study. Haematologica. 2020;105(9):2327-2334.
2. Macfarlane RG, Biggs R. A thrombin generation test. J Clin Pathol. 1953;6(1):3-7.
3. HemkerHC,WillemsGM,B´eguinS.Acomputerassistedmethodto obtain the prothrombin activation velocity in whole plasma inde- pendent of thrombin decay processes. Thromb Haemost. 1986;56(1):9-17.
4. Hemker HC, Wielders S, Kessels H, B´eguin S. Continuous registra- tion of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost .1993;70(4):617-624.
5. Hemker HC, Giesen PL, Ramjee M, et al. The thrombogram: moni- toring thrombin generation in platelet-rich plasma. Thromb Haemost. 2000;83(4):589-591.
6. Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003;1(7):1504-1514.
7. Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41(3):553-558.
8. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365(2):147-156.
9. Tripodi A, Primignani M, Badiali S, et al. Body mass index reduction improves the baseline procoagulant imbalance of obese subjects. J Thromb Thrombolysis. 2019;48(1):52-60.
10. Tripodi A, Branchi A, Chantarangkul V, et al. Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin gener- ation assay. J Thromb Thrombolysis. 2011;31(2):165-172.
11. Tripodi A, Ammollo CT, Semeraro F, et al. Hypercoagulability in patients with Cushing disease detected by thrombin generation
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