Venous thromboembolism. Aspects on risk factors, diagnostic tools and treatment with thrombin inhibition

Abstract

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a multifactorial disease. The aims of the present thesis were to investigate Factor V Leiden and prothrombin G20210A mutations as potential risk factors for VTE during and after major surgery, to compare different D-dimer assays and evaluate their usefulness in the diagnosis of DVT, to investigate clinical effects, safety and pharmacokinetic properties of an oral thrombin inhibitor (ximelagatran) when treating VTE and finally to investigate the usefulness of coagulation assays (APTT and PT) during treatment with thrombin inhibition.In a European population (n=1600) subjected to elective orthopaedic surgery the prothrombin gene G20210A mutation was found to be a risk factor (OR=9.2, p<0.0002) for symptomatic VTE after elective surgery. The Factor V Leiden mutation was found to be a risk factor only for symptomatic PE (OR=5.3, p<0.03). During the 8 to 11-day period with mandatory anticoagulation prophylaxis no significant risk for any of the mutations for objectively verified VTE, mainly consisting of venographic screened DVT, was seen (OR=1.25, p=0.35). Despite establishing these point mutations as genetic risk factors, approximately 90% of the carriers will not suffer a symptomatic postoperative VTE when given prophylaxis and therefore general preoperative screening may be of questionable value.In a population of 95 consecutive patients, undergoing venography because of a suspicion of DVT, 40% of the venographies in our study verified thrombosis. During thrombus formation the simultaneous endogenous fibrinolysis will release fibrin degradation products measurable as plasma D-dimers. The positive predictive values for DVT diagnosis using plasma D-dimer tests are low and insufficient for clinical use when utilising venography verified DVT as the reference. The negative predictive values for the DVT diagnosis was in this study 82-100 % at a cut-off of 0.5 mg/L for conventional ELISAs, rapid membrane and latex tests. Thus, these tests may be one of several useful tools for excluding DVT. In two clinical studies initial treatments of acute DVT (350 patients) and PE (12 patients) with four fixed doses (24 - 60 mg bid) of ximelagatran were evaluated. In the DVT study LMWH/warfarin was used as a comparator. For DVT patients there were no significant differences between the treatment groups in changes of thrombus sizes, bleeding frequencies, clinical effects, mortalities or treatment discontinuations. In the PE treatment (48 mg bid), 11 of 12 patients showed regressed or unchanged scintigrafic signs of PE. Ximelagatran showed a reproducible pharmacokinetic and pharmacodynamic profile over the 6-9 days of treatment. The maximal plasma melagatran concentrations were obtained 2 - 2.4 h after intake and the half-life in plasma was 3.5 - 3.7 h. The onset of action was rapid, measured as prolongations of APTT, and there was a good correlation (R2 = 0.69) between plasma concentrations of melagatran and APTT values. Oral fixed doses were used in the clinical studies without coagulation monitoring. In an in vitro study the effects of melagatran on 17 different prothrombin time assays showed significant differences both in dose-response curves and in effects on INR values. These tests, standardized for treatment with vitamin K antagonists, are not suitable for monitoring the effects of thrombin inhibitors.