Female Gender and Resistance to Activated Protein C (FV:Q506) as Potential Risk Factors for Thrombosis after Elective Hip Arthroplasty

Abstract

SummaryResistance to activated protein C (APC) caused by the R506Q mutation in factor V is the most common inherited risk factor for venous thrombosis. To elucidate whether APC-resistance is a risk factor for venous thrombosis after elective total hip replacement, the association between APC-resistance (presence of FV:Q506 allele) and postoperative thrombosis was investigated in patients (n = 198) randomised to received short (during hospitalisation, n = 100) or prolonged prophylaxis (three weeks after hospitalisation, n = 98) with low molecular weight heparin (LMWH). Among APC-resistant individuals receiving short prophylaxis, 7/10 developed thrombosis as compared to 2/12 receiving long prophylaxis (p <0.0179). Odds ratio for association between APC-resistance and thrombosis in the short prophylaxis group was 4.2 (CI 95% 1.02-17.5) (p <0.0465). Among those receiving prolonged, prophylaxis, there was no increased incidence of thrombosis associated with APC-resistance. Two unexpected observations were made. One was that APC-resistance was much more common in women (19/109) than in men (3/89) (p <0.001). The other was that even women without APC-resistance were much more thrombosis-prone than men. Thus, 24/48 of women with normal FV genotype and short prophylaxis developed thrombosis vs 8/42 among men, p = 0.002. The increased risk of thrombosis associated with female gender and APC-resistance was neutralised by the prolonged treatment. In conclusion, among patients receiving short prophylaxis, female gender was found to be a strong risk factor for venous thrombosis. Even though APC-resistance appeared to be a risk factor for postoperative thrombosis, the uneven distribution of APC-resistance between men and women, taken together with the increased risk of thrombosis among women, precluded valid conclusions to be drawn about the association between APC-resistance and an increased risk of thrombosis. Our results suggest that prolonged prophylaxis with LMWH after hip surgery is more important for women than for men.

Clinical Aspects and Laboratory Problems in Hereditary Thrombophilia

“…According to a recent study, the prophylactic treatment should be prolonged in women with FV Leiden undergoing total hip re- placement. The rate of thrombosis after 1 month of follow-up was higher in women receiving an LMWH during 1 week versus 1 month [77].…”

Genetic Polymorphisms in Venous Thrombosis and Pulmonary Embolism After Total Hip Arthroplasty: A Pilot Study

“…Whereas some authors concentrated their analysis on all DVTs with or without PE, others used symptomatic DVT as the clinical end point, which might lead to different results as discussed subsequently for the factor V Leiden mutation. Except for Svensson et al [36] who reported an association with an OR of 4.2 for a subgroup of patients on short-term prophylaxis, others found no association between the incidence of all DVTs after major orthopaedic surgery and the presence of factor V Leiden mutation or resistance to activated protein C [18,21,23,29,36,40]. Using symptomatic DVT and/or PE as the clinical end point, however, data are more conflicting.…”

“…For other genetic markers, such an association is suspected and discussed controversially, eg, methylenetetrahydrofolate reductase (MTHFR) C677T and/or A1298C and plasminogen activator inhibitor 1 (PAI-1) 4G/5G polymorphisms [1-3, 10, 11, 16, 22, 30, 32, 34, 37, 44]. Results of former studies are conflicting regarding whether the single or combined presence of such genetic mutations may further increase the already very high risk for DVT after major orthopaedic surgery, justifying costly preoperative screening and additional antithrombotic prophylactic measures in these patients [5,6,8,18,20,21,23,29,31,36,[40][41][42][43]. One reason for the conflicting results may be found in the different clinical end points set in the studies varying among venographically diagnosed DVT, clinically symptomatic DVT with or without PE, or symptomatic PE only.…”

“…One reason for the conflicting results may be found in the different clinical end points set in the studies varying among venographically diagnosed DVT, clinically symptomatic DVT with or without PE, or symptomatic PE only. Most of these authors found no association between one of the previously named genetic polymorphisms and the incidence of symptomatic or asymptomatic DVT after major orthopaedic surgery [18,21,23,29,31,36,40,42]. When concentrating their analysis on symptomatic DVT, however, results are conflicting [5,6,8,20,31,40,41].…”

Thrombophilia and venous thromboembolism after total hip or knee replacement surgery: a systematic review

“…One prospective study of symptomatic VTE detected a significant difference in the incidence of symptomatic VTE associated with FVL [4]. The cohort [5][6][7][8], or case-control [9,10] studies using asymptomatic screening for DVT did not, however, find an association between FVL and asymptomatic VTE (Fig. 1).…”