A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology

Abstract

International Normalized Ratio (INR), which standardizes prothrombin time (PT) during oral anticoagulation, has been extended to standardize PT in liver diseases and is included in prognostic models such as the Model for End stage Liver Disease (MELD). However, mechanisms of PT prolongation in liver diseases differ from those involved in oral anticoagulation, and the thromboplastin reagents differ in their sensitivities to these 2 mechanisms. Our aim was to determine whether, in the calibration model for thromboplastins proposed by the World Health Organization, the use of plasmas from patients with liver diseases instead of plasmas from patients on oral anticoagulation could lead to a new INR specific for liver diseases (INR "LD"), achieving a real standardization of PT. First, 5 thromboplastins were calibrated against an international reference using 60 plasmas of patients with liver failure and, in a second step, the variation of PT reported as seconds, the ratio of patient PT to normal PT, See Editorial on Page 295 P rothrombin time (PT) is the usual test for monitoring oral anticoagulation by vitamin K antagonists 1 and is widely adopted to assess the severity of acute and chronic liver injury. 2 PT is the recalcification time of citrated plasma in the presence of a thromboplastin reagent. 3 The term thromboplastin refers to a complex mixture of tissue factor and phospholipids prepared from tissue extracts of animal or human origin. Recent thromboplastins contain recombinant tissue factor. PT is influenced by the levels of the following coagulation factors: I (fibrinogen), II, V, VII, and X, all factors being synthesized by the liver and, among them, 3 (II, VII, and X) being vitamin K dependent. Thromboplastins can vary markedly in their responsiveness to the defects induced by vitamin K antagonist therapy. As a result, the poor agreement between PT in different laboratories whatever the methods of reporting results 4 has led to important differences in oral anticoagulant dosing. 5,6 Standardization of PT reporting in patients on oral anticoagulation has been improved by the calibration model for thromboplastins proposed by the World Health Organization (WHO). 7 This system defines, for a specific thromboplastin reagent, the International Sensitivity Index (ISI) obtained by a calibration using plasmas of patients on stable oral anticoagulant doses, against a WHO international reference thromboplastin. 7 The ISI is a numerical value that reflects the responsiveness of a given thromboplastin to reduction of the vitamin K-dependent coagulation factors; the lower the ISI value, the greater the sensitivity of the reagent. The recommended scale of reporting PT results is

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

“…However, depending on the thromboplastin used in the assay, the INR measured for an individual patient may vary across laboratories [39], thus introducing a bias into the CTP and MELD scores which may affect the priority for liver transplantation [40,41]. There have been attempts to solve this issue by two groups who proposed new systems for INR standardization: the INR-liver (valid for patients with cirrhosis) and the INR-VKA (valid for patient on VKA) [40,41]. These methods have not yet been endorsed by scientific societies or regulatory authorities.…”

“…As previously mentioned, VKA are used in patients with cirrhosis; a further concern is using the INR to report the PT results. The common INR (INR-VKA) is a reliable index of the anti-coagulation level in non-liver disease patients, but may be suboptimal in patients with cirrhosis [40,41].…”

How to report results of prothrombin and activated partial thromboplastin times

“…These variations are likely to change the priority system to allocate organs [20]. Recently, Tripodi et al [21] and Bellest et al [22] independently proposed an alternative calibration model tentatively called INR LIVER (as opposed to the INR VKA ) aimed at solving this problem. The modified system calls for the ISI LIVER being determined by using in the calibration plot the PT for plasmas from patients with chronic liver disease instead of patient stabilized on VKA.…”

Coagulopathy in liver disease: Lack of an assessment tool

“…It is predominantly related to haemodynamic factors, local vascular abnormalities, and Child-Pugh score, which describes the severity of liver disease [77,78] , with a minor role for haemostasis [79] . Furthermore, spontaneous bleeding is less frequent than would be expected from the abnormality shown in laboratory tests.…”