Thrombin generation assay identifies individual variability in responses to low molecular weight heparin in pregnancy: implications for anticoagulant monitoring

Abstract

SummaryLow molecular weight heparin (LMWH) given to inhibit coagulation and reduce the risk of thrombosis, is typically monitored by anti-Xa assay. However, anti-Xa levels may not necessarily provide an accurate measure of coagulation inhibition. Moreover, pregnancy is associated with hypercoagulability, which may compromise the efficacy of LMWH. We looked at the association between anti-Xa levels and parameters of thrombin generation assay [TGA; area under the curve (AUC), peak height (PH) and time to peak (ttP)] using samples from 41 pregnant women receiving LMWH and 40 normal pregnant women controls. TGA results confirmed the physiological hypercoagulability of normal pregnancy (mean normalised values: AUC 119%; PH 157%; ttP 72%). Although anti-Xa measures correlated with all three TGA parameters, this group correlation masked significant inter-individual variability, demonstrated by the R 2 value or coefficient of determination. Anti-Xa levels contributed to 74% of variation in AUC values, 63% of variation in PH values and only 53% of variation in ttP values. The remainder reflects the contribution of patients' intrinsic coagulation status. Hence, some patients with 'safe' anti-Xa levels may potentially be under-anticoagulated, particularly in pregnancy. Measuring coagulability directly with TGA may lower the risk of adverse events due to under-anticoagulation in selected patients.

Thrombin generation assays for optimizing low molecular weight heparin dosing in pregnant women at risk of thrombosis

“…Another important observation arising from our study is that the thrombin generation parameters become more hypercoagulable as pregnancy progress (Chowdary et al, 2015). This, coupled with the fact that the elimination of LMWH increases progressively with gestation, suggests that incremental dosing…”

“…We agree with the authors that anti-Xa activity is not the ideal tool for monitoring low molecular weight heparin (LMWH). However, we would be cautious in accepting their conclusion based on the large variation in timing of blood sampling for peak anti-Xa level (up to 6 h) post-LMWH administration reported by Chowdary et al (2015). Peak anti-Xa activity occurs 3-to 4-h post-LMWH administration, depending on the type of LMWH used (Hirsh et al, 2001).…”

Thrombogenesis in Thrombophilic Pregnancy: Evaluation of Low-Molecular-Weight Heparin Prophylaxis

“…When prothrombin is converted to thrombin, the prothrombin fragment 1 + 2 is released from prothrombin; therefore, F1 + 2 is derived directly from cleavage of prothrombin to thrombin and F1 + 2 is directly proportional to thrombin generation; F1 + 2 is a prethrombotic marker and increased levels of F1 + 2 are widely recognized to be useful to demonstrate a high risk of thrombosis and the existence of a hypercoagulable state even during pregnancy [1,2,3,4,5,6,7,8,9]. F1 + 2 levels can be detected also in the urine of patients affected by VTE [10] and both F1 + 2 and D-dimer plasma levels are inversely correlated to creatinine clearance [11].…”

“…Anti-factor Xa activity can be utilized to determine the degree of anticoagulation in patients receiving LMWH [7]. However, some women with safe anti-Xa levels may potentially be underanticoagulated, particularly in pregnancy [8]. Thus, it is crucial to make available a reliable method to measure coagulability.…”

An effective tool to evaluate the homeostasis during pregnancy: dynamic thrombophotometry (thrombodynamics)

“…[15] пока-зали чувствительность ТГТ к присутствию низкомолеку-лярного гепарина in vitro. К сожалению, на настоящий момент отсутствуют когортные исследования, которые связывали бы клинические исходы с численными значе-ниями параметров данного теста [14].…”