Thrombophilia and location of venous thromboembolism.

Abstract

Several studies have provided evidence of a reduced incidence of pulmonary embolism (PE) in relation to the incidence of deep‐vein thrombosis (DVT) in patients with the factor V Leiden (FVL) G1691A‐mutation [1De Moerloose P. Reber G. Perrier A. Perneger T. Bounameaux H. Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism.Br J Haematol. 2000; 110: 125-9Crossref PubMed Scopus (60) Google Scholar, 2Emmerich J. Rosendaal F.R. Cattaneo M. Margaglione M. De Stefano V. Cumming T. Arruda V. Hillarp A. Reny J.L. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism – pooled analysis of 8 case–control studies including 2310 cases and 3204 controls. Study Group for Pooled‐Analysis in Venous Thromboembolism.Thromb Haemost. 2001; 86: 809-16Crossref PubMed Scopus (0) Google Scholar, 3Lindmarker P. Schulman S. Sten‐Linder M. Wiman B. Egberg N. Johnsson H. The risk of recurrent venous thromboembolism in carriers and non‐carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation.Thromb Haemost. 1999; 81: 684-9Crossref PubMed Scopus (223) Google Scholar, 4Martinelli I. Battaglioli T. Razzari C. Mannucci P.M. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia.J Thromb Haemost. 2007; 5: 98-101Crossref PubMed Scopus (0) Google Scholar, 5Martinelli I. Cattaneo M. Panzeri D. Mannucci P.M. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism.Thromb Haemost. 1997; 77: 440-3Crossref PubMed Google Scholar]. An exception is a Danish study, which could not demonstrate a reduced risk of PE in patients with this defect [6Juul K. Tybjaerg‐Hansen A. Schnohr P. Nordestgaard B.G. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population.Ann Intern Med. 2004; 140: 330-7Crossref PubMed Google Scholar]. The differential anatomic distribution has not been described for the prothrombin G20210A mutation [2Emmerich J. Rosendaal F.R. Cattaneo M. Margaglione M. De Stefano V. Cumming T. Arruda V. Hillarp A. Reny J.L. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism – pooled analysis of 8 case–control studies including 2310 cases and 3204 controls. Study Group for Pooled‐Analysis in Venous Thromboembolism.Thromb Haemost. 2001; 86: 809-16Crossref PubMed Scopus (0) Google Scholar, 3Lindmarker P. Schulman S. Sten‐Linder M. Wiman B. Egberg N. Johnsson H. The risk of recurrent venous thromboembolism in carriers and non‐carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation.Thromb Haemost. 1999; 81: 684-9Crossref PubMed Scopus (223) Google Scholar, 4Martinelli I. Battaglioli T. Razzari C. Mannucci P.M. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia.J Thromb Haemost. 2007; 5: 98-101Crossref PubMed Scopus (0) Google Scholar]. Recently Martinelli et al. [4Martinelli I. Battaglioli T. Razzari C. Mannucci P.M. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia.J Thromb Haemost. 2007; 5: 98-101Crossref PubMed Scopus (0) Google Scholar] reported that the rate of distal DVT was significantly lower than proximal DVT in patients with either FVL mutation or prothrombin mutation in comparison with patients without these mutations. Surprisingly, Klok et al. [7Klok F.A. Huisman M.V. Karami Djurabi R. Tormene D. Simioni P. Prandoni P. Factor V Leiden is associated with more distal location of deep vein thrombosis in the leg.J Thromb Haemost. 2007; 5: O‐S-058Google Scholar] subsequently reported that in another Italian population patients with FVL mutation had a higher proportion of thrombosis with distal vein location. This is of course plausible because it is mainly the proximal DVTs that are associated with occurrence of PE. Moreover, proximal DVT and PE have a higher risk of recurrence than distal DVT, and the former two could therefore, also be more similar in other respects. Conversely, if the reason for proportionally less PE in patients with FVL mutation is associated with the properties of the thrombus, for example being more adherent or more resistant to fragmentation, there may not be any mutation‐associated difference in the propensity to develop proximal vs. distal DVT. We have now analyzed the patient population from the DURAC I trial [8Schulman S. Rhedin A.S. Lindmarker P. Carlsson A. Larfars G. Nicol P. Loogna E. Svensson E. Ljungberg B. Walter H. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.N Engl J Med. 1995; 332: 1661-5Crossref PubMed Scopus (950) Google Scholar] regarding the incidence of different thrombophilic defects and the observed locations of the index event. This was a study with randomization to 6 weeks or 6 months of secondary prophylaxis with vitamin K antagonist after the first episode of DVT or PE in 897 patients. All index events were objectively verified with ascending venography for DVT and with ventilation‐perfusion lung scan for PE. A distal DVT was a filling defect that did not reach proximally of the knee joint space. Patients with deficiency of antithrombin, protein C or protein S were excluded from the trial, and samples for homocystein and FVIII were not obtained. Thus the association between these defects and location of thromboembolism could not be evaluated. We have previously described the methods used for FVL and prothrombin mutation [3Lindmarker P. Schulman S. Sten‐Linder M. Wiman B. Egberg N. Johnsson H. The risk of recurrent venous thromboembolism in carriers and non‐carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation.Thromb Haemost. 1999; 81: 684-9Crossref PubMed Scopus (223) Google Scholar], cardiolipin antibodies IgG [9Schulman S. Svenungsson E. Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group.Am J Med. 1998; 104: 332-8Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar] and plasminogen activator inhibitor type 1 (PAI‐1) [10Schulman S. Wiman B. The significance of hypofibrinolysis for the risk of recurrence of venous thromboembolism. Duration of Anticoagulation (DURAC) Trial Study Group.Thromb Haemost. 1996; 75: 607-11Crossref PubMed Google Scholar]. The definition of 1 unit of cardiolipin antibodies was one standard deviation, and titers of < 5, 5–35, 36–150 and > 150 GPL units were classified as normal range, weak positive, moderate positive and strong positive [9Schulman S. Svenungsson E. Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group.Am J Med. 1998; 104: 332-8Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar]. When the upper limit of normal for PAI‐1 activity (15 U mL–1) was used as cut‐off, there was no statistically significant association with the risk of recurrence as opposed to twice the upper limit of normal as cut‐off (30 U mL–1; P=0.045), and the latter was therefore also used in the present analysis. PAI‐1 and cardiolipin antibodies were analyzed in samples obtained 6 months after the index event in 787 and 810 patients, respectively. The FVL and prothrombin mutations were analyzed in samples obtained 4–9 years after the index event in 495 and 482 patients, respectively. The main reason for lack of sample was death. In addition, for the sub‐study with the mutation analyses we also had excluded patients above 70 years of age. The results are shown in Table 1.Table 1Proportion of different thrombophilic defects according to the location of venous thromboembolismDistal deep‐vein thrombosis (DVT)Proximal DVTPulmonary embolismNumber tested/% abnormalNumber tested/% abnormalNumber tested/% abnormalFactor V Leiden (FVL) mutation heterozygous206/26.2219/28.370/10FVL mutation homozygous206/1.0219/4.170/0Prothrombin mutation heterozygous198/5.6214/6.170/5.7Plasminogen activator inhibitor type 1 > 30 U mL–1304/9.9388/10.895/17Cardiolipin antibodies positive315/11.4398/15.697/10 Open table in a new tab The difference in proportion of any of the defects tested between distal and proximal DVT was not statistically significant (chi‐squared test with Yates correction). There was again a significantly lower proportion of FVL mutation among patients with PE than DVT (P=0.01). On the other hand, there was a trend to more patients with high PAI‐1 activity among patients with PE than with DVT (P=0.09). We would suggest that the findings by Martinelli et al. [4Martinelli I. Battaglioli T. Razzari C. Mannucci P.M. Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia.J Thromb Haemost. 2007; 5: 98-101Crossref PubMed Scopus (0) Google Scholar] and by Klok et al. [7Klok F.A. Huisman M.V. Karami Djurabi R. Tormene D. Simioni P. Prandoni P. Factor V Leiden is associated with more distal location of deep vein thrombosis in the leg.J Thromb Haemost. 2007; 5: O‐S-058Google Scholar] of a lower or higher proportion, respectively, of FVL mutation among patients with distal DVT occurred by chance. Although the definition of distal DVT differed between the three studies discussed, the discordant results speak against an association between presence of thrombophilia and the location of DVT in the leg veins. The author states that he has no conflict of interest.