Alessandra Dell'Era

An Imbalance of Pro- vs Anti-Coagulation Factors in Plasma From Patients With Cirrhosis

BACKGROUND & AIMS Patients with cirrhosis have an increased tendency to develop thromboses despite the longer coagulation times of their plasma, compared with that of healthy individuals. We investigated whether plasma from cirrhotic patients has an imbalance of pro- vs anti-coagulation factors. METHODS We analyzed blood samples from 134 cirrhotic patients and 131 healthy subjects (controls) for levels of pro- and anti-coagulants and for thrombin generation in the presence or absence of thrombomodulin (the main physiologic activator of the protein C anticoagulant pathway). RESULTS The median ratio of thrombin generation (with/without thrombomodulin) was higher in patients (0.80; range, 0.51-1.06) than controls (0.66; range, 0.17-0.95), indicating that cirrhotic patients are resistant to the action of thrombomodulin. This resistance resulted in greater hypercoagulability of plasma from patients of Child-Pugh class C than of class A or B. The hypercoagulability of plasma from patients of Child-Pugh class C (0.86; range, 0.70-1.06) was slightly greater than that observed under the same conditions in patients with congenital protein C deficiency (0.76; range, 0.60-0.93). Levels of factor VIII, a potent pro-coagulant involved in thrombin generation, increased progressively with Child-Pugh score (from Child-Pugh class A to C). Levels of protein C, one of the most potent naturally occurring anti-coagulants, showed the opposite trend. CONCLUSIONS The hypercoagulability of plasma from patients with cirrhosis appears to result from increased levels of factor VIII and decreased levels of protein C-typical features of patients with cirrhosis. These findings might explain the risk for venous thromboembolism in patients with chronic liver disease.

Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis

The diagnosis of an underlying chronic myeloproliferative disorder (CMPD) is often problematic in patients with primary extrahepatic portal vein obstruction (EHPVO) or Budd‐Chiari syndrome (BCS); indeed, conventional clinical and hematological parameters usually yield insufficient information. To assess the diagnostic contribution of the gain‐of‐function mutation V617F of the JAK2 gene, 93 patients with EHPVO or BCS were investigated. JAK2 V617F was identified in 35.6% of 73 patients with EHPVO and in 40% of 20 patients with BCS. Taking the JAK2 mutation as a test with the highest positive predictive value for the diagnosis of CMPD, conventional clinical‐hematological parameters had a sensitivity for CMPD lower than 48%. Bone marrow (BM) histology provided a diagnosis of CMPD in 41/74 (55.4%) patients, with a sensitivity of 93.5%. Clonality of hematopoiesis as assessed by granulocyte X‐chromosome inactivation was present in 65.1% of 43 informative female patients, with a sensitivity of 86.6%. By resolving the sensitivity bias of the JAK2 mutation with the results of BM histology and clonality assay, CMPD was diagnosed in 53% of patients with EHPVO or BCS. In conclusion, CMPD is the major cause of primary EHPVO or BCS. JAK2 V617F is a very reliable and noninvasive molecular marker for CMPD and should be used as a first test for diagnosis. (HEPATOLOGY 2006;44:1528–1534.)

Risk factors for thrombophilia in extrahepatic portal vein obstruction

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain‐of‐function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3–7.0) and 4.4 (95% CI, 3.3–5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8–17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1–18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1–6.4) and for lower limb DVT of 7.5 (95% CI, 4.4–13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9–4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden. (HEPATOLOGY 2005;41:603–608.)

The international normalized ratio calibrated for cirrhosis (INRliver) normalizes prothrombin time results for model for end‐stage liver disease calculation

The model for end‐stage‐liver‐disease (MELD) is a mathematical score used to prioritize patients for liver transplantation and includes results for creatinine, bilirubin, and prothrombin time (PT) expressed as international normalized ratio (INR). The rationale of using the MELD rests on the assumption that the score would be the same across the country if the methods used to measure the variables yield the same numerical results regardless of the testing laboratory. Evidence was provided that specific methodologies may influence the MELD, and the PT‐INR was identified as the most important. This study was designed to provide information on the between‐thromboplastin variability and to explore alternatives to obviate such variability. Fifty‐seven patients with cirrhosis were selected, and their PTs were measured with 7 thromboplastins. The thromboplastins were previously calibrated by testing plasmas from patients on vitamin K antagonists and healthy subjects to assign the international sensitivity index (ISIvka) needed to convert PT into INR. Each of the thromboplastins was also assigned an ISIliver by substituting in the calibration the plasmas from vitamin K antagonist patients with plasmas from patients with cirrhosis. INR and MELD values for individual patients were calculated by using the ISIvka or the ISIliver. The mean INRvka obtained with the 7 thromboplastins were significantly different (P < 0.001). Conversely, the mean INRliver were not. Similarly, the mean MELDvka were significantly different (P < 0.001), but those differences were abrogated for the MELDliver. Conclusion: The alternative thromboplastin calibration using plasmas from patients with cirrhosis instead of from vitamin K antagonist patients is feasible and may resolve the variability of the MELD to prioritize patients for transplantation. (HEPATOLOGY 2007.)

Good long-term outcome of Budd-Chiari syndrome with a step-wise management

Budd‐Chiari syndrome (BCS) is a rare, life‐threatening disease caused by obstruction of hepatic venous outflow. The aim of the study was to assess long‐term outcome and identify prognostic factors in BCS patients managed by a step‐wise approach using anticoagulation, angioplasty/thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), and orthotopic liver transplantation (OLT). We reviewed long‐term data on 157 patients previously included by the European Network for Vascular Disorders of the Liver, a multicenter prospective study of newly diagnosed BCS patients in nine European countries. Patients were followed for a median of 50 months (range, 0.1‐74.0). During the study, 88 patients (56%) received at least one invasive intervention (22 patients angioplasty/thrombolysis, 62 TIPS, and 20 OLT) and 36 (22.9%) died. Most interventions and/or deaths occurred in the first 2 years after diagnosis. The Rotterdam score was excellent in predicting intervention‐free survival, and no other variable could significantly improve its prognostic ability. Moreover, BCS‐TIPS prognostic index (PI) score (based on international normalized ratio, bilirubin, and age) was strongly associated with survival and had a discriminative capacity, which was superior to the Rotterdam score. Conclusions: The current study confirms, in a large cohort of patients with BCS recruited over a short period, that a step‐wise treatment approach provides good long‐term survival. In addition, the study validates the Rotterdam score for predicting intervention‐free survival and the BCS‐TIPS PI score for predicting survival. (HEPATOLOGY 2013;)

The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters

BACKGROUND Thromboelastometry allows continuous registration of the blood viscoelastic changes upon activation by cephaline or tissue-factor plus calcium-chloride. The technique is used as a near-patient-testing device to guide transfusion in cardiac surgery or liver transplantation and less to investigate hemostasis in acquired or congenital coagulopathies. AIMS (i) Review of the coagulopathy associated with cirrhosis and (ii) report on its investigation by thromboelastometry in comparison with conventional coagulation parameters. METHODS We investigated citrated blood samples from 51 adult cirrhotics for the following thromboelastometry parameters: coagulation-time (CT), clot-formation-time (CFT), maximum-clot-firmness (MCF). RESULTS Relatively few patients [14/51(27%)] were identified as abnormal by CT; in contrast, a greater proportion were identified by the CFT [41/51(80%)] or MCF [39/51(76%)]. CFT and MCF were correlated with the platelet-count, antithrombin and fibrinogen. Prothrombin time (PT) was correlated with CFT and MCF. None of the coagulation parameters were correlated with CT. The correlation of the Child-Pugh-score (taken as index of severity) versus MCF or PT was -0.457(p < 0.001) or 0.484(p < 0.001), suggesting MCF as a suitable prognostic index. CFT and MCF, but not CT obtained ROC curves that were useful to distinguish patients from healthy individuals. CONCLUSIONS Thromboelastometry, currently used to assist liver transplantation is also suitable for investigating stable cirrhosis. CFT and MCF are the most interesting parameters to be considered for future clinical studies needed to assess their value as measures of bleeding-risk and prognosis in this category of patients.

Detection of the Imbalance of Procoagulant Versus Anticoagulant Factors in Cirrhosis by a Simple Laboratory Method

Patients with cirrhosis possess an imbalance in procoagulant versus anticoagulant activity due to increased factor VIII and decreased protein C. This imbalance can be detected by thrombin‐generation assays performed in the presence/absence of thrombomodulin (predicate assay) that are not readily available in clinical laboratories. We sought to assess this hypercoagulability with a simpler thrombin‐generation assay performed in the presence/absence of Protac, a snake venom that activates protein C in a manner similar to thrombomodulin (new assay). We analyzed blood from 105 patients with cirrhosis and 105 healthy subjects (controls). Results for the predicate‐assay or the new‐assay were expressed as ratio (with:without thrombomodulin) or as Protac‐induced coagulation inhibition (PICI%). By definition, high ratios or low PICI% translate into hypercoagulability. The median(range) PICI% was lower in patients (74% [31%‐97%]) than controls (93% [72%‐99%]; P < 0.001), indicating that patients with cirrhosis are resistant to the action of Protac. This resistance resulted in greater plasma hypercoagulability in patients who were Child class C than those who were A or B. The hypercoagulability of Child C cirrhosis (63% [31%‐92%]) was similar to that observed for patients with factor V Leiden (69% [15%‐80%]; P = 0.59). The PICI% values were correlated with the levels of protein C (rho = 0.728, P < 0.001) or factor VIII (rho = −0.517, P < 0.001). Finally, the PICI% values were correlated with the predicate assay (rho = −0.580, P < 0.001). Conclusion: The hypercoagulability of plasma from patients with cirrhosis can be detected with the new assay, which compares favorably with the other markers of hypercoagulability (i.e., high factor VIII and low protein C) and with the predicate‐assay based on thrombin‐generation with/without thrombomodulin. Advantages of the new assay over the predicate assay are easy performance and standardized results. Prospective trials are needed to ascertain whether it is useful to predict thrombosis in patients with cirrhosis. HEPATOLOGY 2010

High levels of factor VIII and risk of extra-hepatic portal vein obstruction

BACKGROUND/AIMS High levels of coagulation factor VIII are a risk factor for lower-limb deep vein thrombosis (DVT). Their role in extra-hepatic portal vein obstruction (EHPVO) is not established. METHODS Factor VIII was measured in 85 patients with EHPVO (primary in 58 and complicating liver cirrhosis in 27), in 200 with lower-limb DVT, in 108 with liver cirrhosis without thrombosis and in 200 healthy controls. RESULTS Factor VIII levels were significantly higher in patients with primary EHPVO (138 IU/dL, range 86-366), EHPVO and cirrhosis (147 IU/dL, 95-242), lower-limb DVT (140 IU/dL, 64-400) and cirrhosis alone (160 IU/dL, 43-446) than in controls (112 IU/dL, 62-250, p<0.001). When factor VIII exceeded 129 IU/dL (66th percentile), the odds ratios were 10.5 (95%CI 3.3-33.4) for primary EHPVO, 6.0 (1.2-30.7) for EHPVO and cirrhosis, 5.0 (2.6-9.4) for lower-limb DVT. After exclusion of the effect of the acute phase reaction, the odds ratio for primary EHPVO was 4.2 (0.8-22.7), and was 8.7 (0.9-80.5) after exclusion also of patients with chronic myeloproliferative disorders. CONCLUSIONS High factor VIII levels are independently associated with an increased risk for EHPVO. The risk of EHPVO increased with increasing factor VIII levels and was only partially dependent on the acute phase reaction.

MPL and JAK2 exon 12 mutations in patients with the Budd-Chiari syndrome or extrahepatic portal vein obstruction

To the editor: The Budd-Chiari syndrome (BCS) and extrahepatic portal vein obstruction (EHPVO) are splanchnic vein thromboses (SVT) that may occur as presenting complications of undiagnosed chronic myeloproliferative disorders (CMPD). Diagnosis of the underlying CMPD may be difficult because

Portal vein thrombosis in inflammatory bowel diseases: A single-center case series

BACKGROUND AND METHODS Portal vein thrombosis (PVT) has been reported as a complication of IBD in some case reports. We describe the presentation, diagnostic approaches, underlying risks factors and clinical outcome of 8 IBD patients with PVT. CASE-SERIES: The patients presented with partial PVT (4 patients) or portal cavernoma. Five patients had undergone surgery. In 2 patients portal biliopathy was diagnosed after detection of PVT. In 4 patients, the diagnosis of PVT was made while IBD was in remission. Five patients showed at least one risk factor for hypercoagulability: lupus anti-coagulant (one patient), increased von Willebrand factor (2 patients) or homocysteine levels (4 patients). Four patients received anticoagulant therapy for 6 months. None experienced other thrombotic events during a median of 5 years (range 2-8 years). CONCLUSION PVT is a potential complication of IBD, usually associated with acquired or inherited risks factors for hypercoagulability and with a benign outcome.