Integrated laboratory coagulation tests in hypercoagulation diagnosis and thrombosis risk assessment. Part II. The sensitivity of integral tests to hypercoagulable states

In the second part we present a review of the existing data about ability of integrated tests, as already introduced in clinical practice, and the new (test of thrombin generation, thromboelastography, thrombodynamics, perfusion chamber) to assess the risk of thrombosis in different pathologies. We can conclude that the existing integrated tests can be an important tool in the diagnosis of hypercoagulation. However, lack of standardization prevents their use: various tests and modifications of each test are different in sensitivity and specificity for each pathological condition. Furthermore, even in situations where the tests can reliably identify a group of patients with different degrees of thrombosis risk, their use in clinical practice is often difficult, since the differences between these groups were statistically significant, but the normal range and patients significantly overlap

Integrated laboratory coagulation tests in hypercoagulation diagnosis and thrombosis risk assessment. Part I. The pathophysiology of thrombosis and hypercoagulation

Thrombosis is a fatal hemostatic disorders occurring in various conditions ranging from pregnancy and surgery to cancer, sepsis and heart attack. Despite the availability of different anticoagulants and accumulated clinical experience, proving their effectiveness, thrombosis remains a major cause of morbidity and mortality. This is largely due to the fact that conventional laboratory coagulation tests are not sufficiently sensitive to the hypercoagulable state, and they are difficult to use for assessing the risk of thrombosis. Specific molecular markers (D-dimers, fibrinopeptide, thrombin-antithrombin complex) are more effective, but also have a large number of disadvantages. A possible solution is the use of integrated test, which simulate in vitro the majority of the physiological coagulation processes. In the first part of this paper the biochemical processes that cause the risk of thrombosis were discussed

New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling

Factor Xa is a serine protease representing a crucial element in the coagulation process and an attractive target for anticoagulant therapy. At the present time there are several chemical classes of factor Xa inhibitors with proven activity. Furthermore, three factor Xa inhibitors have been approved for the medical use to date. However, therapy with these medications is accompanied by substantial adverse effects. In this background, the structure-based computational approach combining molecular docking and semiempirical quantum chemical calculations was applied for a search for new effective factor Xa inhibitors. We have undertaken a few virtual screening procedures to select potential candidates for synthesis and subsequent testing. The first screen of the focused library resulted in identifying 20 compounds among which 7 compounds showed the noticeable inhibition of factor Xa at maximal concentrations, allowed by solubility. The subsequent additional screens identified 20 additional candidates. Of these, 5 substances were shown to be capable of inhibiting factor Xa at 5 μM. The best two found 1,2,3,4-tetrahydroquinoline derivatives identified by means of modelling have demonstrated IC50 values in the micromolar range. One of them turned out to be selective factor Xa inhibitor over trypsin, factors IIa, IXa and XIa. © 2019 Elsevier Inc