Impaired platelet‐dependent thrombin generation associated with thrombocytopenia is improved by prothrombin complex concentrates in vitro

Abstract

Background Impaired thrombin generation (TG) in patients with acquired coagulopathy, is due to low coagulation factors and thrombocytopenia. The latter is typically treated with platelet transfusions and the former with plasma and occasionally with prothrombin complex concentrates (PCCs). We hypothesized that manipulating the concentrations of coagulation factors might result in restoration of platelet‐dependent TG over and above that of simple replacement therapy. Objective To investigate the influence of PCCs on impaired TG secondary to thrombocytopenia. Methods TG was evaluated by thrombin generation assay using a thrombocytopenia model in which normal plasma samples with varying platelet counts (20‐300 × 109/L) were spiked with PCCs (25%‐150% increase in plasma PCC levels). Results PCCs and platelets significantly increased TG in a dose‐dependent manner in vitro. Two‐way repeated measures of analysis of variance showed variance in peak height, area under the curve, time to peak, and velocity. This variance explained, respectively, by levels of PCC was 47, 59, 25 and 53%; by platelet count was 45, 28, 44, and 14%; by the combination was 80, 67, 70, and 62% variance; and a combination with additional interaction was 91, 84, 76, and 68%. TG at a platelet count 40 × 109/L with an approximate 25% increase in PCC concentration was similar to TG at 150 × 109/L. Similarly, patient samples spiked ex vivo with PCCs also showed highly significant improvements in TG. Conclusions Impaired TG of thrombocytopenia is improved by PCCs, supporting the need for additional studies in complex coagulopathies characterized by mild to moderate thrombocytopenia and abnormal coagulation.

In vitro Effect of Dalteparin and Argatroban on Hemostasis in Critically Ill Sepsis Patients with New-Onset Thrombocytopenia

“…By dividing patients in two groups according to peak thrombin, our study demonstrated that the decreases in platelet count within 24 hours prior to inclusion were lower in patients with peak thrombin levels !100 nM than in patients with levels <100 nM. Previous studies suggest that higher platelet counts increase the rate and peak of thrombin generation, [41][42][43] however, these studies focused on stable platelet counts and not new-onset thrombocytopenia, which demonstrates a more dynamically developed hemostatic abnormality. Platelets were depleted in plasma samples by centrifugation prior to analysis eliminating their contribution to thrombin generation.…”

Perioperative thrombocytopenia: review of current recommendations and implementation in clinical practice

“…Згідно з клітинною моделлю коагуляції комплекси факторів Xa/Va на поверхні активованих тромбоцитів генерують викид тромбіну, який потім запускає стійке гемостатичне утворення фібринового згустку [75] і залежить не лише від коливань рівня протромбіну, але й від кількості тромбоцитів [76]. Нещодавно було продемонстровано в експериментальних умовах, що порушення тромбоцитзалежних ланок гемостазу внаслідок тромбоцитопенії можна відновити шляхом додавання концентрату протромбінового комплексу з чотирма факторами [76]. Це експериментальне відкриття вимагає подальшої клінічної оцінки, щоб визначити, чи можна використовувати концентрат протромбінового комплексу для зменшення хірургічної кровотечі в пацієнтів з тромбоцитопенією.…”

Perioperative thrombocytopenia

“…According to the cell-based model for coagulation, factor Xa/Va complexes on the surface of activated platelets generate a burst of thrombin, which then triggers stable hemostatic fibrin clot formation [75]. As such, TG is not only dependent on variations in prothrombin levels, but also on platelet count [76]. It was recently demonstrated in an experimental setting that impaired platelet-dependent TG due to thrombocytopenia can be restored by the addition of four factors prothrombin complex concentrate (PCCs) [76].…”

“…As such, TG is not only dependent on variations in prothrombin levels, but also on platelet count [76]. It was recently demonstrated in an experimental setting that impaired platelet-dependent TG due to thrombocytopenia can be restored by the addition of four factors prothrombin complex concentrate (PCCs) [76]. This experimental finding requires further clinical evaluation to determine if PCCs can be used to decrease surgical bleeding in thrombocytopenic patients.…”