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

Abstract

Thrombocytopenia is common among critically ill sepsis patients, while they also hold an increased risk for thromboembolic events. Thus, the choice of anticoagulant prophylaxis for this patient population is challenging. We investigated the in vitro effect of low-molecular-weight heparin (dalteparin) and direct thrombin inhibitor (argatroban) on the hemostasis in blood from sepsis patients with new-onset thrombocytopenia. Thrombocytopenia was defined as a platelet count drop of ≥30% and/or from >100x109/L to 30-100x109/L within 24 hours prior to inclusion. We included five healthy individuals and ten patients. Analysis of thrombin generation (Calibrated Automated Thrombogram), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex levels, and thromboelastometry (ROTEM®) were performed. Based on dose-response-relationships investigated in healthy blood, patient samples were spiked with prophylactic (0.25 IU/mL) and therapeutic (0.75 IU/mL) dalteparin and low (0.25 µg/mL) and high (0.50 µg/mL) argatroban concentrations, each with a sample without anticoagulant. In patients, the endogenous thrombin potential was markedly lower in therapeutic dalteparin samples than in samples without anticoagulant [median (range): 29 (0-388) vs. 795 (98-2121) nM×min]. In high argatroban concentration samples, thrombin lag time was longer than in samples without anticoagulant [median (range): 15.5 (10.5-20.2) vs. 5.3 (2.8-7.3) min]. Dalteparin and argatroban both increased clotting time but did not affect maximum clot firmness in the ROTEM INTEM® assay. Six patients had elevated TAT and eight patients had elevated F1+2. In conclusion, dalteparin mainly affected the amount of thrombin generated and argatroban delayed clot initiation in critically ill sepsis patients with new-onset thrombocytopenia. Neither anticoagulant affected clot strength.

A Nonbactericidal Anionic Antimicrobial Peptide Provides Prophylactic and Therapeutic Efficacies against Bacterial Infections in Mice by Immunomodulatory–Antithrombotic Duality

“…11 Haematological abnormalities, a prothrombotic condition related with mortality, are among the most common complications of severe infections. 11,12 The bacterially mediated pro-inflammatory responses invariably cause coagulation and/or hemostatic disorders, which are mainly related to the uncontrolled activation of the coagulation cascade and platelet function, as well as dysfunction of the natural anticoagulation pathways (tissue factor pathway inhibitor, protein C system, and antithrombotic system). 13,14 The dysregulation may lead to thrombosis, and there is much fibrin formation and deposition in nonbleeding locations.…”

“…In addition to the lack of effective antibiotics, increased mortality from bacterial infection is also associated with various uncontrolled complications . Haematological abnormalities, a prothrombotic condition related with mortality, are among the most common complications of severe infections. , The bacterially mediated pro-inflammatory responses invariably cause coagulation and/or hemostatic disorders, which are mainly related to the uncontrolled activation of the coagulation cascade and platelet function, as well as dysfunction of the natural anticoagulation pathways (tissue factor pathway inhibitor, protein C system, and antithrombotic system). , The dysregulation may lead to thrombosis, and there is much fibrin formation and deposition in nonbleeding locations .…”

“…In addition to the lack of effective antibiotics, increased mortality from bacterial infection is also associated with various uncontrolled complications . Haematological abnormalities, a prothrombotic condition related with mortality, are among the most common complications of severe infections. , The bacterially mediated pro-inflammatory responses invariably cause coagulation and/or hemostatic disorders, which are mainly related to the uncontrolled activation of the coagulation cascade and platelet function, as well as dysfunction of the natural anticoagulation pathways (tissue factor pathway inhibitor, protein C system, and antithrombotic system). , The dysregulation may lead to thrombosis, and there is much fibrin formation and deposition in nonbleeding locations . Evidence indicates that appropriate and timely antithrombotic therapy, including antiplatelet and anticoagulant agents, appears to be essential for the outcomes of patients with severe infection. , Several cationic AMPs with anticoagulant activity have been described in vitro . , However, there is no information about the effects of anionic AMPs on coagulation cascades, platelet function, or anticoagulant pathways.…”