Systems Biology Approach for Personalized Hemostasis Correction.

The correction of blood coagulation impairments of a bleeding or thrombotic nature employs standard protocols where the type of drug, its dose and the administration regime are stated. However, for a group of patients, such an approach may be ineffective, and personalized therapy adjustment is needed. Laboratory hemostasis tests are used to control the efficacy of therapy, which is expensive and time-consuming. Computer simulations may become an inexpensive and fast alternative to real blood tests. In this work, we propose a procedure to numerically define the individual hemostasis profile of a patient and estimate the anticoagulant efficacy of low-molecular-weight heparin (LMWH) based on the computer simulation of global hemostasis assays. We enrolled a group of 12 patients receiving LMWH therapy and performed routine coagulation assays (activated partial thromboplastin time and prothrombin time) and global hemostasis assays (thrombodynamics and thrombodynamics-4d) and measured anti-Xa activity, fibrinogen, prothrombin and antithrombin levels, creatinine clearance, lipid profiles and clinical blood counts. Blood samples were acquired 3, 6 and 12 h after LMWH administration. We developed a personalized pharmacokinetic model of LMWH and coupled it with the mechanism-driven blood coagulation model, which described the spatial dynamics of fibrin and thrombin propagation. We found that LMWH clearance was significantly lower in the group with high total cholesterol levels. We generated an individual patient's hemostasis profile based on the results of routine coagulation assays. We propose a method to simulate the results of global hemostasis assays in the case of an individual response to LMWH therapy, which can potentially help with hemostasis corrections based on the output of global tests.

Impaired platelet activity and hypercoagulation in healthy term and moderately preterm newborns during the early neonatal period.

BACKGROUND: Preterm newborns are at thrombohemorrhagic risk during the early neonatal period. Taking into account the lack of informative tools for the laboratory diagnosis of hemostasis disorders in newborns, our goal was to determine the baseline values of thrombodynamics and platelet functional activity in healthy term and moderately preterm newborns during the early neonatal period future potential clinical use of these tests. METHODS: Coagulation was assessed using an integral assay of thrombodynamics and standard coagulation assays, and platelet functional activity was estimated by flow cytometry. RESULTS: Hypercoagulation of newborns, represented by a significantly higher clot growth velocity and the presence of spontaneous clots in the thrombodynamics, was combined with platelet hypoactivity. Granule release, phosphatidylserine exposure, and the ability to change shape upon activation were decreased in the platelets of moderately preterm newborns. The platelet function remained at the same level over the first four days of life, whereas the hypercoagulation became less pronounced. CONCLUSIONS: The hemostasis of newborns is characterized by hypercoagulation combined with reduced platelet functional activity. Moderately preterm and term newborns do not differ in the parameters of coagulation, while some of the functional responses of platelets are lower in moderately preterm newborns than in term.

Thrombodynamics-A new global hemostasis assay for heparin monitoring in patients under the anticoagulant treatment.

BACKGROUND: Heparin therapy and prophylaxis may be accompanied by bleeding and thrombotic complications due to individual responses to treatment. Dosage control based on standard laboratory assays poorly reflects the effect of the therapy. The aim of our work was to compare the heparin sensitivity of new thrombodynamics (TD) assay with sensitivity of other standard and global coagulation tests available to date. STUDY POPULATION AND METHODS: A total of 296 patients with high risk of venous thromboembolism (deep vein thrombosis (DVT), early postoperative period, hemoblastosis) were enrolled in the study. We used a case-crossover design to evaluate the sensitivity of new thrombodynamics assay (TD) to the hemostatic state before and after unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) therapy/prophylaxis and to compare it with the activated partial thromboplastin time (APTT), anti-Xa activity test, thrombin generation test (TGT) and thromboelastography (TEG). A receiver operating characteristic (ROC) curve analysis was used to evaluate changes before and after heparin prophylaxis and therapy. Blood was sampled before heparin injection, at the time of maximal blood heparin concentration and before the next injection. RESULTS: Hypercoagulation before the start of heparin treatment was detected by TD, TGT and TEG but not by APTT. The area under the ROC curve (AUC) was maximal for TD and anti-Xa, intermediate for TGT and TEG and minimal for APTT. CONCLUSIONS: These results indicate that TD has a high sensitivity to the effects of UFH and LMWH after both prophylactic and therapeutic regimes and may be used for heparin monitoring.

The laboratory control of anticoagulant thromboprophylaxis during the early postpartum period after cesarean delivery.

INTRODUCTION: The incidence of venous thromboembolism (VTE) after cesarean section is up to 0.6%, and the widespread use of cesarean section draws attention to this group. The dosage and duration of low-molecular-weight heparin (LMWH) prophylaxis after delivery is estimated by anamnestic risk-scales; however, the predictive potency for an individual patient's risk can be low. Laboratory hemostasis assays are expected to solve this problem. The aim of this study was to estimate the potency of tests to reflect the coagulation state of patients receiving LMWH in the early postpartum period. MATERIALS AND METHODS: We conducted an observational study on 97 women undergoing cesarean section. Standard coagulation tests (Fg, APTT, prothrombin, D-dimer), an anti-Xa assay, rotation thromboelastometry and thrombodynamics/thrombodynamics-4D were performed. Coagulation assay parameters were compared in groups formed in the presence or absence of LMWH to estimate the laboratory assays' sensitivity to anticoagulation. RESULTS: Coagulation assays revealed hypercoagulation after delivery and a tendency toward normalization of coagulation during early postpartum. The thromboprophylaxis results revealed a higher percentage of coagulation parameters within the normal range in the LMWH group. CONCLUSION: This research is potentially beneficial for the application of thrombodynamics and thrombodynamics-4D in monitoring coagulation among patients with high VTE risk who receive thromboprophylaxis with heparin.

Thromboelastography, thrombin generation test and thrombodynamics reveal hypercoagulability in patients with multiple myeloma.

Patients with multiple myeloma (MM) are at increased risk of venous thromboembolism. Therefore, adequate laboratory control of hemostasis and subsequent adjustments of anticoagulant therapy are necessary. We studied hemostasis changes using thromboelastography (TEG), thrombin generation test (TGT) and thrombodynamics (TD) in primary MM patients (PMMpt, n=25) and patients in remission (RMMpt, n=34) during blood stem cell (BSC) mobilization. TD and TEG reveal hypercoagulability in PMMpt (*p<0.05) in relation to healthy volunteers. There was no difference in any of the tests between PMMpt and RMMpt. We detected no heparin effect in 22% of patients one day after the onset of the prophylactic heparin treatment (500 IU/h) during BSC mobilization; tests shifted toward the hypercoagulability in 75% of patients one day after cyclophosphamide (4 g/m2) chemotherapy. Global hemostasis tests were in good agreement with each other, revealed hypercoagulability and heparin "resistance" in patients with MM and may be useful for therapy individualization.