Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma

Abstract

Cirrhosis is characterized by a complex coagulation defect leading to the prolongation of the prothrombin and activated partial thromboplastin times (PT and APTT). Arbitrary PT cut-off values are still used as a yardstick to guide treatment with fresh-frozen plasma (FFP) or other pro-coagulant agents in patients undergoing invasive procedures. No randomized studies on the FFP efficacy are available, and are unlikely to be carried out because of their complex organization. An interim solution could be to evaluate the in vitro thrombin generation in plasmas from patients with cirrhosis when mixed with appropriate amounts of pooled normal plasma (PNP). The PT, APTT and thrombin generations in the presence of thrombomodulin were examined in 58 patients with cirrhosis and 24 healthy subjects both before and after mixing their plasmas with PNP at a proportion of 4 + 1 (patient + PNP), chosen to mimic in vivo conditions when patients are treated with 10 ml/kg of FFP. The PT and APTT, which were abnormal in the majority of unmixed patient plasmas were shortened considerably, but did not normalize completely when mixed with PNP. Thrombin generation, which was already within normal limits in all unmixed patient plasmas, remained essentially unchanged after mixing with PNP. In conclusion, thrombin generation in patients with cirrhosis does not appreciably change after in vitro addition of PNP despite PT and APTT shortening would suggest otherwise. These results question the validity of the PT as a stand-alone test to guide transfusion of FFP in the setting of chronic liver disease.

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

“…The infusion of <500 mL of FFP seldom corrects the PT by more than 2-3 s [142,147]. In vitro, the addition of FFP to plasma of patients with cirrhosis proved ineffective in increasing thrombin generation [148,149]. It is important to realize that cut-off values for PT employed to trigger infusion are arbitrarily set and not based on clinical trial data.…”

Thrombin generation in different cohorts: Evaluation of the haemostatic potential

“…If those results were to be extrapolated to patients with coagulopathy of liver disease, which has long been considered mainly as a bleeding disorder [132], it could lead to revisiting the current clinical practice of routinely administering blood products to patients with CLD prior to invasive procedures in order to minimize the risk of bleeding. The value of routine transfusions has already been challenged [143,144] and revisiting this clinical practice would spare unnecessary trans-fusions, as well as avoiding adverse transfusion-related reactions, unmotivated delay in surgeries etc.…”

“…Thrombin generation (in PRP) does not increase after addition of one adult standard platelet dose in thrombocytopenic patients [143] nor after mixing plasma from cirrhotic patients with plasma from normal subjects in a concentration corresponding to 10 ml/kg body weight [144]. Those results challenge the existing concept of routinely administering platelets or plasma to cirrhotic patients prior to invasive procedures.…”

Dispelling myths about coagulation abnormalities in internal medicine

“…23,25,26 This paradigm shift in medical understanding is now well researched and several publications attest to the fact that abnormal PT and APTT in liver disease patients do not correlate with bleeding in any way. 23,25,27 For this reason, fresh frozen plasma administration noticed after an infection or infl ammatory illness as a transient phenomenon. This is certainly the case in intensive care units, where abnormalities in the clotting screen are most often noted.…”

“…-Platelet count (>100 × 10 9 /l = 0, <100 × 10 9 /l = 1, <50 × 10 9 /l = 2) to correct these results is probably futile and will only delay any procedures that may need to be carried out urgently. 27,28 In this regard, the position paper on liver biopsy of the American Association for the Study of Liver Diseases states: 'the use of prophylactic or rescue strategies such as plasma, fi brinolysis inhibitors, or recombinant factors should be considered in specifi c situations, although their effectiveness remains to be established (Class IIa, Level C).' 29 The exact contribution of coagulopathy in liver disease can be identifi ed only by global coagulation assays that take into consideration the haemostatic system as a whole.…”