Ilona T. A. Pereboom

Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests

BACKGROUND & AIMS Patients with liver disease often show substantial changes in their hemostatic system, which may aggravate further during liver transplantation. Recently, thrombin generation in patients with stable disease was shown to be indistinguishable from controls provided thrombomodulin, the natural activator of the anticoagulant protein C system, was added to the plasma. These results indicated that the hemostatic balance is preserved in patients with liver disease, despite conventional coagulation tests suggest otherwise. METHODS Here we examined thrombin generation profiles in serial plasma samples taken from ten consecutive patients undergoing liver transplantation. RESULTS At all time points, the endogenous thrombin potential (ETP) was slightly lower compared to healthy volunteers, despite substantially prolonged PT and APTT values. However, when thrombin generation was tested in the presence of thrombomodulin, the ETP was equal to or even higher than that in healthy subjects. In fact, thrombin generation was hardly affected by thrombomodulin, while thrombin generation in healthy subjects decreased profoundly upon the addition of thrombomodulin. In patients undergoing liver transplantation, efficient thrombin generation in the presence of thrombomodulin may be explained by decreased levels of protein C, S, and antithrombin, and by elevated levels of FVIII. CONCLUSIONS Thrombin generation in patients undergoing liver transplantation is equal or even superior to thrombin generation in healthy volunteers when tested in the presence of exogenous thrombomodulin. These results support the recently advocated restrictive use of plasma during liver transplantation and warrants further study of the prophylactic use of anticoagulants to reduce thromboembolic complications after transplantation.

Platelet Transfusion During Liver Transplantation Is Associated with Increased Postoperative Mortality Due to Acute Lung Injury

BACKGROUND: Platelet transfusions have been identified as an independent risk factor for survival after orthotopic liver transplantation (OLT). In this study, we analyzed the specific causes of mortality and graft loss in relation to platelet transfusions during OLT. METHODS: In a series of 449 consecutive adult patients undergoing a first OLT, the causes of patient death and graft failure were studied in patients who did or did not receive perioperative platelet transfusions. RESULTS: Patient and graft survival were significantly reduced in patients who received platelet transfusions, compared with those who did not (74% vs 92%, and 69% vs 85%, respectively at 1 yr; P < 0.001). Lower survival rates in patients who received platelets were attributed to a significantly higher rate of early mortality because of acute lung injury (4.4% vs 0.4%; P = 0.004). There were no significant differences in other causes of mortality between the two groups. The main cause of graft loss in patients receiving platelets was patient death with a functioning graft. CONCLUSIONS: These findings suggest that platelet transfusions are an important risk factor for mortality after OLT. The current study extends previous observations by identifying acute lung injury as the main determinant of increased mortality. The higher rate of graft loss in patients receiving platelets is related to the higher overall mortality rate and does not result from specific adverse effects of transfused platelets on the grafted liver.

Platelets in liver transplantation: friend or foe?

Apart from the well‐known role of blood platelets in hemostasis, there is emerging evidence that platelets have various nonhemostatic properties that play a critical role in inflammation, angiogenesis, tissue repair and regeneration, and ischemia/reperfusion (I/R) injury. All these processes may be involved in the (patho)physiological alterations occurring in patients undergoing liver transplantation. Experimental and clinical research points toward a dualistic role of platelets in patients undergoing liver transplantation, resulting in both beneficial and detrimental effects. Although a low platelet count is generally considered a risk factor for perioperative bleeding, recent studies have indicated that platelet function in patients with cirrhosis may not be as abnormal as previously assumed. Platelet transfusions are frequently considered in liver transplant recipients to correct low platelet counts and to prevent bleeding; however, evidence‐based transfusion thresholds are lacking, and the other detrimental and nonhemostatic properties of platelets are generally not weighed in this respect. First, platelets have been shown to contribute to I/R injury of the liver graft via induction of sinusoidal endothelial cell apoptosis. Second, platelet transfusion has been identified as an independent risk factor for reduced survival via mechanisms that are not completely understood yet. On the other hand, recent studies indicate that platelets are critically involved in restoration after liver injury and in liver regeneration via serotonin‐mediated mechanisms. These findings make platelets both friend and foe in liver transplantation. The scientific challenge will be to further dissect the mechanisms and clinical relevance of these contrasting roles of platelets in liver transplantation. Liver Transpl 14:923–931, 2008.

Development of a Severe von Willebrand Factor/ADAMTS13 Dysbalance During Orthotopic Liver Transplantation

Patients with liver disease show profound changes in their hemostatic system, which may further change during liver transplantation. We previously demonstrated that highly elevated levels of the platelet adhesive protein von Willebrand factor (VWF) in patients with cirrhosis lead to an increased VWF‐dependent platelet deposition under flow as compared to healthy controls. In this study we examined VWF parameters during the course of liver transplantation. We collected serial plasma samples from 20 patients undergoing liver transplantation in which we determined plasma levels of VWF and the VWF‐cleaving protease ADAMTS13. Furthermore, we performed functional tests of VWF‐dependent platelet adhesion. We found persistently elevated levels of VWF during and after liver transplantation. The capacity of VWF to interact with platelets normalized during the course of transplantation, and flow‐mediated VWF‐dependent platelet adhesion remained at levels far exceeding those observed in healthy individuals during and after transplantation. Plasma levels of ADAMTS13 dropped during transplantation, and in four patients levels below 10% of normal were observed after reperfusion. We observed the development of a hyperreactive primary hemostatic system, as evidenced by high levels of fully functional VWF and a temporary ADAMTS13 deficiency, during liver transplantation, and speculate that these changes contribute to postoperative thrombotic complications.

Interlaboratory variability in assessment of the model of end‐stage liver disease score

Background: The model of end‐stage liver disease (MELD) score is nowadays widely used to prioritize patients for liver transplantation.

Aprotinin and nafamostat mesilate in liver surgery: Effect on blood loss

The origin of blood loss during liver surgery is multifactorial. Surgical skill, technique, anesthesiological care, but also hyperfibrinolysis have been shown to play a role in the origin of bleeding during partial hepatectomy and liver transplantation. The latter has provided the scientific basis for the prophylactic use of antifibrinolytic drugs, such as aprotinin and nafamostat mesilate in liver surgery. Recently however, concern has been voiced about potential risks associated with aprotinin, including renal failure and thromboembolic events. In this review we discuss the efficacy and safety issues of aprotinin and nafamostat mesilate in liver surgery. We identified a total of 19 studies on the use of either aprotinin or nafamostat mesilate in liver surgery reported in the time period between 1966 and July 2006. The use of aprotinin or nafamostat mesilate in partial hepatectomies was studied in three studies. In 16 studies the use of aprotinin in liver transplantation was investigated. With respect to partial hepatectomy, improvements in surgical technique and anesthesiological care seem to be more important in reducing blood loss than the use of the antifibrinolytic drugs. Aprotinin may be indicated in a selected group of patients with cirrhosis undergoing liver resection, but further studies in this specific group of patients will be needed. In liver transplantation, the use of aprotinin is associated with a significant reduction in blood loss and transfusion requirements of around 30–40%. Results of prospective studies do not provide support for safety concerns as no increased risk for thromboembolic events or renal dysfunction has been observed in liver transplant patients treated with aprotinin. In conclusion, there is currently no scientific support for the routine use of aprotinin or nafamostat mesilate in patients undergoing partial hepatectomy, whereas the efficacy of aprotinin in liver transplantation is well established. More studies will be needed to address the safety aspects of aprotinin in patients undergoing liver surgery in more detail.

No evidence for systemic platelet activation during or after orthotopic liver transplantation.

Platelet function is thought to deteriorate during liver transplantation as a result of platelet activation and proteolysis of platelet receptors by plasmin following reperfusion. However, this hypothesis has never been formally tested. Twenty patients undergoing a first or second liver transplant were included in the study. Blood samples were taken at standardized time points during transplantation and up to 10 days after transplantation. Platelet activation was assessed by detection of the activation markers P‐selectin and activated integrin αIIbβ3 with flow cytometry. Proteolytic cleavage of platelet receptors was assessed by flow cytometry measurement of the constitutively expressed platelet receptors glycoprotein Ibα and integrin αIIbβ3. In addition, using enzyme‐linked immunosorbent assay techniques, we measured plasma levels of platelet activation products β‐thromboglobulin and platelet factor 4 and plasma levels of cleaved fragments of glycoproteins Ibα and V. Flow cytometry analyses provided no evidence of substantial platelet activation during transplantation. In fact, the expression of activated integrin αIIbβ3 decreased postoperatively; this indicated that platelets were in a slightly activated state prior to surgery. Plasma levels of β‐thromboglobulin and platelet factor 4 also substantially decreased after transplantation. In addition, no changes were observed in the constitutively expressed platelet receptors or in the plasma levels of platelet receptor fragments, and this indicated a lack of substantial receptor proteolysis. In conclusion, no evidence was found for significant activation of circulating blood platelets or the proteolysis of key platelet receptors during liver transplantation. These findings suggest that the platelet functional capacity does not decrease during liver transplantation. Liver Transpl 15:956–962, 2009.

Prothrombotic Gene Polymorphisms: Possible Contributors to Hepatic Artery Thrombosis After Orthotopic Liver Transplantation

Background. Gene polymorphisms involved in hemostasis have been associated with an increased risk of thromboembolic events. The aim of this study was to assess whether prothrombotic gene polymorphism is a risk factor for hepatic vascular thrombosis after orthotopic liver transplantation (OLT). Methods. In a series of 421 transplant procedures, genomic DNA was available for genotyping in 381 donors (91%) and 382 recipients (91%). In donors and recipients, the presence of factor V Leiden mutation, the prothrombin G20210A, and the factor XIII G100T polymorphisms were identified. In recipients, the C677T methylenetetrahydrofolate reductase (MTHFR), the platelet glycoprotein integrin &agr;2 C807T, the integrin &bgr;3 C1565T, and the thrombospondin 4 A387P polymorphisms were identified. Clinical data were obtained from a prospectively maintained database and medical records. All recipients underwent screening for hepatic vascular thrombosis using Doppler ultrasonography, followed by catheter or computed tomography angiography if indicated. Results. In an overall analysis, none of the polymorphisms were associated with hepatic vascular thrombosis. When thrombosis in the first 7 days after OLT was excluded, we found a 3- to 7-fold increased risk for hepatic artery thrombosis (HAT) in association with factor V Leiden or factor XIII G100T (donor), and MTHFR C677T (recipient). Conclusions. The presence of factor V Leidenorfactor XIII G100T in the donor liver or MTHFR C677T in the recipient is associated with an increased risk of HAT after OLT. However, because the prevalence of these polymorphisms is low and the overall impact on the incidence of HAT is minimal, routine screening for these genotypes seems not justified.