Armando Tripodi

Update of the guidelines for lupus anticoagulant detection

Summary.  One of the conclusions of the subcommittee meeting on Lupus Anticoagulant/Phospholipid dependent antibodies, held in Geneva on 2007, was the need to update the guidelines on Lupus Anticoagulant (LA) detection. Particular emphasis was given to several aspects discussed in this official communication. A new paragraph is dedicated to the patient selection, and aims to minimize inappropriate requests for LA testing. Modalities for blood collection and processing are fully delineated and the choice of tests is limited to dRVVT and a sensitive aPTT. Calculation of cut‐off values for each diagnostic step are clearly stated. A final paragraph reports the interpretation of the results in general and in particular situations.

Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests

The role played by coagulation defects in the occurrence of bleeding in cirrhosis is still unclear. This is partly due to the lack of tests that truly reflect the balance of procoagulant and anticoagulant factors in vivo. Conventional coagulation tests such as prothrombin time and activated partial thromboplastin time are inadequate to explore the physiological mechanism regulating thrombin, because they do not allow full activation of the main anticoagulant factor, protein C, whose levels are considerably reduced in cirrhosis. We used a thrombin generation test to investigate the coagulation function in patients with cirrhosis. Thrombin generation measured without thrombomodulin was impaired, which is consistent with the reduced levels of procoagulant factors typically found in cirrhosis. However, when the test was modified by adding thrombomodulin (i.e., the protein C activator operating in vivo), patients generated as much thrombin as controls. Hence, the reduction of procoagulant factors in patients with cirrhosis is compensated by the reduction of anticoagulant factors, thus leaving the coagulation balance unaltered. These findings help clarify the pathophysiology of hemostasis in cirrhosis, suggesting that bleeding is mainly due to the presence of hemodynamic alterations and that conventional coagulation tests are unlikely to reflect the coagulation status of these patients. In conclusion, generation of thrombin is normal in cirrhosis. For a clinical validation of these findings, a prospective clinical trial is warranted where the results of thrombin generation in the presence of thrombomodulin are related to the occurrence of bleeding. (HEPATOLOGY 2005;41:533–558.)

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.

Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management

Normal coagulation has classically been conceptualized as a Y‐shaped pathway, with distinct “intrinsic” and “extrinsic” components initiated by factor XII or factor VIIa/tissue factor, respectively, and converging in a “common” pathway at the level of the FXa/FVa (prothrombinase) complex. Until recently, the lack of an established alternative concept of hemostasis has meant that most physicians view the “cascade” as a model of physiology. This view has been reinforced by the fact that screening coagulation tests (APTT, prothrombin time – INR) are often used as though they are generally predictive of clinical bleeding. The shortcomings of this older model of normal coagulation are nowhere more apparent than in its clinical application to the complex coagulation disorders of acute and chronic liver disease. In this condition, the clotting cascade is heavily influenced by numerous currents and counter‐currents resulting in a mixture of pro‐ and anticoagulant forces that are themselves further subject to change with altered physiological stress such as super‐imposed infection or renal failure. This report represents a summary of a recent multidisciplinary symposium held in Charlottesville, VA. We present an overview of the coagulation system in liver disease with emphasis on the limitations of the current clinical paradigm and the need for a critical re‐evaluation of the current tenets governing clinical practice. With the realization that there is often limited or conflicting data, we have attempted to represent diverse opinion and experience from the perspectives of both hepatology and hematology beginning with a brief update on the physiology of normal coagulation. (HEPATOLOGY 2006;44:1039–1046.)

Hemostasis and thrombosis in patients with liver disease: The ups and downs

Patients with chronic or acute liver failure frequently show profound abnormalities in their hemostatic system. Whereas routine laboratory tests of hemostasis suggest these hemostatic alterations result in a bleeding diathesis, accumulating evidence from both clinical and laboratory studies suggest that the situation is more complex. The average patient with liver failure may be in hemostatic balance despite prolonged routine coagulation tests, since both pro- and antihemostatic factors are affected, the latter of which are not well reflected in routine coagulation testing. However, this balance may easily tip towards a hypo- or hypercoagulable situation. Indeed, patients with liver disease may encounter both hemostasis-related bleeding episodes as well as thrombotic events. During the 3rd International Symposium on Coagulopathy and Liver disease, held in Groningen, The Netherlands (18-19 September 2009), a multidisciplinary panel of experts critically reviewed the current data concerning pathophysiology and clinical consequences of hemostatic disorders in patients with liver disease. Highlights of this symposium are summarized in this review.

Measuring oral direct inhibitors of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis

Oral direct inhibitors (ODIs) of thrombin and factor Xa are now approved as anticoagulant drugs. The first two drugs to complete phase III clinical trials for thromboprophylaxis in orthopaedic surgery and treatment of patients with atrial fibrillation or venous thromboembolism were dabigatran and rivaroxaban. These small molecules are given at fixed dose with no requirement for monitoring as pharmacokinetic and pharmacodynamic responses are reliably predicted in patients with adequate renal function who are not taking other interacting drugs. However, there will be clinical circumstances in specific patients when measurement of the anticoagulant effect of an ODI will be required.

Questions and answers on the use of dabigatran and perpectives on the use of other new oral anticoagulants in patients with atrial fibrillation: A consensus document of the Italian Federation of Thrombosis Centers (FCSA)

Dabigatran and other new oral anticoagulants (OAC) represent a step forward in stroke prevention in patients with atrial fibrillation (AF). They indeed have been shown to be an alternative to vitamin K antagonists (VKAs) without the burden of laboratory control. However, these new drugs compete with an effective and well-established therapy, thus bringing about a series of questions and doubts. In this report members of the board of the Italian Federation of Thrombosis Centers (FCSA) answer some questions every clinician might be confronted with.

Hypercoagulability in cirrhosis: causes and consequences†

Summary.  Decreased levels of most coagulation factors and thrombocytopenia are the main haemostatic abnormalities of cirrhosis. As a consequence, this condition was, until recently, considered as the prototype acquired coagulopathy responsible for bleeding. However, recent evidence suggests that it should, rather, be regarded as a condition associated with normal or even increased thrombin generation. The bleeding events that occur in these patients should, therefore, be explained by the superimposed conditions that frequently occur in this setting. Due to elevated levels of factor VIII (procoagulant driver) in combination with decreased protein C (anticoagulant driver), which are typically found in patients with cirrhosis, a procoagulant imbalance, defined as a partial resistance to the in vitro anticoagulant action of thrombomodulin, can be demonstrated. Whether this in vitro hypercoagulability is truly representative of what occurs in vivo remains to be established. However, the hypothesis that it may have clinical consequences is attractive and deserves attention. The possible consequences that we discuss herein include whether (i) cirrhosis is a condition associated with increased risk of venous thromboembolism or portal vein thrombosis; (ii) the hypercoagulability associated with cirrhosis has any other role outside coagulation (i.e. progression of liver fibrosis); and (iii) anticoagulation should be used in cirrhosis. Although apparently provocative, considering anticoagulation as a therapeutic option in patients with cirrhosis is now supported by a rationale of increasing strength. There may be subgroups of patients who benefit from anticoagulation to treat or prevent thrombosis and to slow hepatic fibrosis. Clinical studies are warranted to explore these therapeutic options.

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.)

Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance A Multicenter Collaborative Family Study

Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.