Increased anticoagulant response to low‐molecular‐weight heparin in plasma from patients with advanced cirrhosis

Abstract

Summary. Introduction: Cirrhotic patients may present thrombotic complications that warrant anticoagulant therapy. However, the efficacy of low-molecular-weight heparin (LMWH) in this clinical setting is still unclear. Aims/methods: To evaluate the in vitro effect of LMWH on thrombin generation (TG) in cirrhotic patients at different stages of liver disease. Thirty cirrhotics (10 Child Pugh A, 10 Child Pugh B and 10 Child Pugh C), 10 subjects with inherited type 1 antithrombin (AT) defect and 10 healthy controls were studied. TG was determined at baseline and with anti-Xa levels after the addition of enoxaparin at 0.35 and 0.7 U anti-Xa mL. The endogenous thrombin potential (ETP) ratio at 0.35 and 0.7 U anti-Xa mL was obtained by dividing ETP with LMWH by ETP at baseline. Results: Mean AT levels in all cirrhotic subgroups and in patients with AT deficiency were significantly lower than in controls. The 0.35 ETP ratio was significantly lower in cirrhotic patients than in controls (0.26 ± 0.1 vs. 0.48 ± 0.1, P < 0.001) and the reduction paralleled the severity of liver disease, in spite of the concomitant decrease in AT and anti-Xa activity. AT-deficient subjects showed a significantly increased 0.35 ETP ratio compared with both cirrhotic patients and controls (0.69 ± 1 vs. 0.26 ± 0.1, P < 0.001, and vs. 0.48 ± 0.1, P = 0.04 respectively). LMWH at 0.7 U anti-Xa mL completely inhibited TG in 9/30 cirrhosis patients with more advanced liver disease (Child Pugh B and C), whereas complete TG abolition was seen in only 1/10 controls. Conclusions: Cirrhotic patients show an increased response to LMWH, which correlates with the severity of liver disease, in spite of reduced AT and anti-Xa activity levels. Thrombin generation may be a useful tool to monitor the response to LMWH in cirrhotic patient

Is there a rationale for treatment of chronic liver disease with antithrombotic therapy?

“…Indeed, by using TGT, we recently demonstrated that the capacity of LMWH to inhibit thrombin formation in plasma of patients with chronic liver disease in vitro was consistent among samples of patients and controls, with the exception of patients with severe cirrhosis who showed a decreased response to the anticoagulant action of the drugs [123]. Interestingly, when using the same test, another group had found a more profound and disease stage-dependent anticoagulant effect of the drugs in cirrhotic plasma compared to normal plasma [124]. This difference in results may be attributed to different pre-analytical conditions highlighting, as with all assays, the necessity for methodological standardization in order to compare or interpret future in vivo dose-response studies of antithrombotic agents in cirrhosis.…”

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

“…In nonrandomized studies [44,45], LMWH administration at a fixed dose was effective and safe in patients with established PVT. In vitro the anti-Xa assay proved suboptimal for monitoring LMWH use [46,47], while TGA was more appropriate [47]. An in vitro study also suggested that, despite of a lower anti-thrombin level, plasma from patients with cirrhosis was more responsive to LMWH than that from healthy subjects [47].…”

“…In vitro the anti-Xa assay proved suboptimal for monitoring LMWH use [46,47], while TGA was more appropriate [47]. An in vitro study also suggested that, despite of a lower anti-thrombin level, plasma from patients with cirrhosis was more responsive to LMWH than that from healthy subjects [47]. The only available randomized trial showed that LMWH at a fixed dose and without laboratory monitoring was effective and safe in preventing PVT in patients with cirrhosis [48].…”

Intensive Care Therapy for Patients with Advanced Liver Diseases

“…In absence of previous history and/or other risk factors for hemorrhagic complications [21,22], low-molecular-weight heparin likely represents the safest choice of systemic anticoagulation in cirrhotic patients with extensive portal vein (and/or mesenteric) thrombosis without increasing the risk for VB [23]. However, clinicians should always be aware of the fact that (despite decreased antithrombin III concentrations) its anticoagulation effect in vivo remains practically unaffected [24]. More aspects of 'hemostasis dysregulation' are shown by Drolz et al [25] in this focus issue of Visceral Medicine.…”