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Plasma From Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin.

ABSTRACT: Recombinant human soluble thrombomodulin (ART-123) is an anticoagulant and anti-inflammatory agent clinically used for treatment of disseminated intravascular coagulation. Preclinical studies have shown that ART-123 reduces hepatic ischemia/reperfusion. Although ART-123 may therefore have clinical benefit in orthotopic liver transplantation, the substantial alterations in the hemostatic system may complicate its use in this setting. Here, we studied the in vitro effect of ART-123 on coagulation of patients with end-stage liver disease undergoing liver transplantation. Ten patients with end-stage liver disease undergoing liver transplantation were included in this study. Plasma samples of 10 healthy individuals were included to establish reference values. Different concentrations of ART-123 were added to plasma samples, and peak thrombin generation and clot lysis times (CLTs) were determined. In patient samples, plasma was profoundly resistant to the anticoagulant action of ART-123, as reflected by significantly higher median inhibitory concentration (IC50 ) values of peak thrombin generation compared with controls. This might be partially explained by low levels of protein C, protein S, and elevated levels of factor VIII during transplantation. Intraoperative levels of thrombin activatable fibrinolysis inhibitor were significantly lower when compared with controls. However, ART-123-dependent prolongation of CLTs was not significantly different from healthy controls. In conclusion, this study suggests that ART-123 is unlikely to provoke bleeding in patients undergoing liver transplantation because proposed clinical dosages have a virtually absent anticoagulant effect in these patients. Clinical studies are required to confirm the safety of ART-123 and efficacy on alleviating ischemia/reperfusion injury during liver transplantation.

SUBMITTER: Burlage LC

PROVIDER: S-EPMC6590179 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Plasma From Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin.

Burlage Laura C LC Bos Sarah S Adelmeijer Jelle J Sakai Takumi T Porte Robert J RJ Lisman Ton T

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 20190201 2

Recombinant human soluble thrombomodulin (ART-123) is an anticoagulant and anti-inflammatory agent clinically used for treatment of disseminated intravascular coagulation. Preclinical studies have shown that ART-123 reduces hepatic ischemia/reperfusion. Although ART-123 may therefore have clinical benefit in orthotopic liver transplantation, the substantial alterations in the hemostatic system may complicate its use in this setting. Here, we studied the in vitro effect of ART-123 on coagulation ...[more]

PMID: 30067306

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Project description:Clinical monitoring of cerebral blood flow (CBF) autoregulation in patients undergoing liver transplantation may provide a means for optimizing blood pressure to reduce the risk of brain injury. The purpose of this pilot project is to test the feasibility of autoregulation monitoring with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) in patients undergoing liver transplantation and to assess changes that may occur perioperatively.We performed a prospective observational study in 9 consecutive patients undergoing orthotopic liver transplantation. Patients were monitored with TCD and NIRS. A continuous Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity and between MAP and NIRS data, rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Both Mx and COx were averaged and compared during the dissection phase, anhepatic phase, first 30 min of reperfusion, and remaining reperfusion phase. Impaired autoregulation was defined as Mx ? 0.4.Autoregulation was impaired in one patient during all phases of surgery, in two patients during the anhepatic phase, and in one patient during reperfusion. Impaired autoregulation was associated with a MELD score >15 (p = 0.015) and postoperative seizures or stroke (p < 0.0001). Analysis of Mx categorized in 5 mmHg bins revealed that MAP at the lower limit of autoregulation (MAP when Mx increased to ? 0.4) ranged between 40 and 85 mmHg. Average Mx and average COx were significantly correlated (p = 0.0029). The relationship between COx and Mx remained when only patients with bilirubin >1.2 mg/dL were evaluated (p = 0.0419). There was no correlation between COx and baseline bilirubin (p = 0.2562) but MELD score and COx were correlated (p = 0.0458). Average COx was higher for patients with a MELD score >15 (p = 0.073) and for patients with a neurologic complication than for patients without neurologic complications (p = 0.0245).These results suggest that autoregulation is impaired in patients undergoing liver transplantation, even in the absence of acute, fulminant liver failure. Identification of patients at risk for neurologic complications after surgery may allow for prompt neuroprotective interventions, including directed pressure management.

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Plasma From Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin.

Publications

Plasma From Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin.

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