Routine coagulation assays underestimate levels of antithrombin‐dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis

Abstract

Summary There is increasing recognition that thrombotic complications may occur in patients with cirrhosis, and literature on antithrombotic treatment in these patients is rapidly emerging. Due to extensive haemostatic changes in patients with cirrhosis, careful monitoring of anticoagulant therapy may be required. Recent data suggest that plasma levels of low molecular weight heparin (LMWH) are substantially underestimated by the anti‐activated factor X (anti‐Xa) assay in patients with cirrhosis. We studied the in vitro recovery of antithrombin (AT)‐dependent and –independent anticoagulant drugs in plasma from 26 patients with cirrhosis and 30 healthy controls and found substantially reduced anti‐Xa levels when AT‐dependent anticoagulant drugs were added to the plasma of patients with cirrhosis. LMWH (0·2 U/ml) had the poorest recovery in plasma from patients with cirrhosis (0·13 ± 0·06 U/ml, compared to 0·23 ± 0·03 U/ml in controls, P < 0·0001), followed by unfractionated heparin and fondaparinux. In contrast, the recovery of rivaroxaban and dabigatran was identical between patients and controls. These data suggest that the anti‐Xa assay cannot be used to monitor AT‐dependent anticoagulant drugs in patients with cirrhosis, as it substantially underestimates drug levels. The direct factor Xa and IIa inhibitors, however, may be monitored through the respective anti‐Xa and anti‐IIa assays in patients with cirrhosis.

Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis

“…varices), but also to a loss of buffer capacity, in the sense that small variations of a pro- and anticoagulant protein will result more easily in an unbalanced situation. Therefore, we can expect that patients react differently to anticoagulation treatment than healthy controls, as shown in recent literature [44]. The most obvious case is the decreased effectiveness of treatment with heparins, because heparin acts by increasing the AT activity [45–47].…”

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

“…In following of these general limitations, our group has investigated whether chronic liver disease-related hemostatic changes affect the reliability of the assay to guide LMWH dosage [122]. We found that the anti-FXa assay systematically underestimated the LMWH dose administered in vitro to plasma of cirrhotic patients (without impaired renal function).…”

Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis

“…These results suggest that anticoagulant treatment with these direct factor Xa inhibitors will likely not result in overanticoagulation, with a potentially increased bleeding risk, provided drug levels remain in the target range. Careful monitoring of drug levels, for example, by anti-Xa testing, 6 1 and subsequent response by the authors is reflective of the growing interest in the use of nontraditional anticoagulants for treatment of portal and superior mesenteric vein thrombosis (PVT/SMV) in patients with cirrhosis. Both factor Xa inhibitors exhibit reliable pharmacokinetics and pharmacodynamics, with a linear relation between plasma concentration of the drug and anticoagulant activity.…”