Evaluation of procoagulant imbalance in Cushing's syndrome after short- and long-term remission of disease.

OBJECTIVE: Patients with Cushing's syndrome (CS) are at high risk of venous thromboembolism related to a hypercoagulability due to procoagulant imbalance. However, whether these alterations are reversible after disease remission is still unclear. The endogenous thrombin potential (ETP) measured with and without the addition of thrombomodulin provides a global representation of coagulation and previous data confirmed hypercoagulable profile in patients with active hypercortisolism. Aim of this study was to assess the short- and long-term modification of ETP in patients with CS after disease remission. DESIGN AND METHODS: Nineteen patients with CS for whom surgical remission was achieved, were prospectively evaluated for clinical characteristics, cortisol secretion profile and ETP at different time points: (i) before surgical intervention; (ii) after 6 months and (iii) 5 years from the time of persistent remission. Nineteen healthy subjects matched for age and gender were also evaluated as control group. RESULTS: Before surgery, patients showed higher ETP-ratio (with/without thrombomodulin) than controls (0.62 ± 0.09-vs-0.56 ± 0.09, p = 0.034). No significant correlation between ETP-ratio and cortisol secretion was found. 6 months after remission, ETP-ratio was still significantly increased compared to controls (0.64 ± 0.09-vs-0.56 ± 0.09, p = 0.01), but was similar to baseline (0.64 ± 0.09-vs-0.62 ± 0.09, p = 0.87). At 5 years, ETP-ratio showed a significant decrease (0.55 ± 0.14-vs-0.62 ± 0.09, p = 0.02) and was comparable to controls (0.55 ± 0.14-vs-0.56 ± 0.09, p = 0.7). CONCLUSIONS: Plasma hypercoagulability detected in patients with active hypercortisolism persists at short-term evaluation and seems to be completely reversible after long-term remission of disease. These data, as part of a whole evaluation of thrombotic risk, can contribute to make appropriate therapeutic choice in these patients.

The thrombin generation assay distinguishes inhibitor from non-inhibitor patients with severe haemophilia A.

INTRODUCTION: Patients with haemophilia A (HA) have impaired thrombin generation (TG) capacity and TG assay (TGA) values are linearly related to plasma factor VIII (FVIII) levels. AIM: This study carried out in patients with unmeasurable FVIII (<1 IU dL(-1) ) was aimed at unravelling any difference in TG capacity in patients with or without inhibitors. METHODS: Blood samples were collected from patients in a non-bleeding state, after a 5-day wash-out period from last treatment. RESULTS: TGA was performed in 102 patients with severe HA (15% with high-responding inhibitors; 51% with null F8 mutations, that as expected were more prevalent in inhibitor than in non-inhibitor patients). TG capacity was significantly lower in inhibitor than non-inhibitor patients and in those with null mutations than in those with non-null mutations. When the TG capacity was evaluated only in patients with null mutations with and without inhibitors it was lower in the presence of inhibitors. CONCLUSIONS: This study shows a greater TG impairment in inhibitor patients irrespective of FVIII levels, inhibitor titre and F8 mutation type, suggesting a role for the TGA in unravelling functional interferences of anti-FVIII inhibitors on coagulation system activation.

Low thrombin generation during major orthopaedic surgery fails to predict the bleeding risk in inhibitor patients treated with bypassing agents.

INTRODUCTION: In the presence of high-titre inhibitors, haemostatic bypassing agents are used to control bleeding and perform surgery. In this setting, no specific laboratory test is yet available to guide drug choice, monitor treatment efficacy and predict the risk of bleeding. AIM: The aims of this study, carried out in patients candidate to orthopaedic surgery, were to assess the dose-dependent increase in thrombin generation (TG) after infusion of bypassing agents and to evaluate whether or not a correlation existed between the haemostatic efficacy of bypassing therapies and perioperative TG values. METHODS AND RESULTS: TG was measured in 16 inhibitor patients, 10 of whom underwent 11 major orthopaedic procedures. In the non-bleeding state, TG significantly improved 30 min after whichever dose (P < 0.01), with no dose-response relationship when values obtained after different rFVIIa doses were compared. TG significantly improved 30 min after the preoperative bolus (P < 0.05), while during the postoperative period TG values measured before and after dosing did not differ. Moreover, postoperative TG values were similar or even more impaired (P ≤ 0.05) than those measured before preoperative dosing. No difference was found by comparing procedures with and without bleeding complications and yet no bleeding occurred in spite of persistently low TG values in one-third of procedures. CONCLUSION: This study fails to support a definite role for the TG assay as a reliable laboratory tool to monitor the haemostatic efficacy of bypassing therapies and as a predictor of the risk of bleeding in inhibitor patients using these agents during orthopaedic surgery.