Factor V Leiden and Fatal Pulmonary Embolism

Summary

To investigate whether the factor V Leiden mutation increases the risk of fatal pulmonary emboli, we determined the presence of the factor V Leiden mutation in pathology material from two series of autopsies of patients from the Leiden University Hospital, The Netherlands. The first series consisted of consecutive autopsies in which pulmonary emboli were mentioned in the autopsy report; most patients of this series had major underlying disease. The second series consisted of autopsies in patients younger than age 70 in which pulmonary emboli were the sole cause of death and no major acquired risk factor for venous thrombosis was present. Extraction of DNA was done on newly prepared tissue from archival paraffin blocks. In the first series, the presence of factor V Leiden was determined in 44 patients, 1 of whom carried the mutation (2.3 percent; 95% confidence interval 0.06 to 12.0 percent). This prevalence is not different from the general population prevalence in The Netherlands. In the second series, factor V Leiden could be determined in 30 patients of whom 3 carried the mutation (10 percent; 95% confidence interval 2.1 to 26.5 percent), which would lead to a threefold relative risk. A large number of patients with diverse psychiatric diagnoses was present in the second series (eleven). We conclude that in the presence of severe illness, the factor V Leiden mutation plays no additional role in the development of pulmonary emboli. The relative risk of the very rare fatal pulmonary embolus that is the sole cause of death might also be less than the relative risk for deep-vein thrombosis in carriers of the factor V Leiden mutation.

^* Current address: Dr. P. H. Reitsma, the Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands

• References

• 1 Bertina RM, Koeleman RPC, Koster T, Rosendaal FR, Dirven RJ, Ronde H de, Velden PA van der, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C.. Nature 1994; 369: 64-7.
• 2 Greengard JS, Sun X, Xu X, Fernández JA, Griffin JH, Evatt B. Activated protein C resistance caused by Arg506Gln mutation in factor Va.. Lancet 1994; 343: 1361-2.
• 3 Voorberg J, Roelse J, Koopman R, Büller H, Berends F, Cate JW ten, Mertens K, Mourik JA van. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V.. Lancet 1994; 343: 1535-6.
• 4 Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis.. Lancet 1994; 343: 1536-8.
• 5 Kalafatis M, Bertina RAM, Rand MD, Mann KG. Characterisation of the molucular defect in factor VR506Q.. J Biol Chem 1995; 270: 4053-7.
• 6 Nicolaes GAF, Tans G, Thomassen LGD, Hemker HC, Pabinger I, Varadi K, Schwarz HP, Rosing J. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor Va^R506Q by activated protein C.. J Biol Chem 1995; 270: 21158-66.
• 7 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.. Proc Natl Acad Sci USA 1993; 90: 1004-8.
• 8 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden.. Lancet 1995; 346: 1133-4.
• 9 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (APC-resistance).. Blood 1995; 85: 1504-8.
• 10 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis.. N Engl J Med 1994; 330: 517-22.
• 11 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.. Lancet 1994; 344: 1454-7.
• 12 Hellgren M, Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives.. Am J Obstet Gynecol 1995; 173: 210-3.
• 13 Hirsch DR, Mikkola KM, Marks PW, Fox EA, Dormfman DM, Ewenstein BM, Goldhaber SZ. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden.. Am Heart J 1996; 131: 1145-8.
• 14 Rintelen C, Mannhalter C, Ireland H, Lane DA, Knöbl P, Lechner K, Pabinger I. Oral contraceptives enhance the risk of clinical manifestations of venous thrombosis at a young age in females homozygous for factor V Leiden.. Brit J Haematol 1996; 93: 487-90.
• 15 Ridker PM, Hennekens Ch H, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.. N Engl J Med 1995; 332: 912-7.
• 16 Desmarais S, Moerloose P, Reber G, Minazio P, Perrier A, Bounameaux H. Resistance to activated protein C in an unselected population of patients with pulmonary embolism.. Lancet 1996; 347: 1374-6.
• 17 Manten B, Westendorp RGJ, Koster T, Reitsma PH, Rosendaal FR. Risk factor profiles in patients with different clinical manifestations of venous thromboembolism.. Thromb Haemost 1996; 76: 510-3.
• 18 Martinelli I, Cattaneo M, Panzeri D, Mannucci PM. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism.. Thromb Haemost 1997; 77: 440-3.
• 19 Shibata DK, Arnheim N, Martin WJ. Detection of human papilloma virus in paraffin embedded tissue using the polymerase chain reaction.. J Exp Med 1988; 167: 225-30.
• 20 Limpens J, Beelen M, Stad R, Haverkort M, van Krieken JHJM, van Ommen GJB, Kluin PM. Detection of the t (14;18) transformation in frozen and formalin-fixed tissue.. Diagnos Mol Pathol 1993; 2: 99-107.
• 21 Koeleman BP, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families.. Blood 1994; 84: 1031-5.
• 22 Webb JS, Standen GR, Collins CMP, Case CP. Postmortem diagnosis of factor V Leiden from paraffin embedded tissue.. J Clin Pathol: Mol Pathol 1996; 49: M180-1.
• 23 Hindersin P, Siegmund R, Körting HJ. Thrombophile Diathesen als Hämostasestörungen bei akuten Psychosen.. Pyschat Neurol med Psychol (Leipzig) 1984; 36: 702-9.
• 24 Ziegler HK. Lungenembolie aus Sicht des Pathologen.. Med Klin 1977; 72: 1063-70.
• 25 Meier-Ewert K, Baumgart HH, Friedenberg P. Thromboembolische Komplikationen bei neuro- und thymoleptischer Behandlung.. Dtsch Med Wschr 1967; 92: 2174-8.
• 26 Lal S, Bleiman M, Brown GN. Pulmonary embolism in psychiatric patients.. J Am Geriatric Society 1966; 14: 1138-43.
• 27 Scholz V. Über thromboembolische Komplikationen unter neuroleptischer Medikation.. Der Nervenarzt 1967; 38: 174-7.
• 28 Kendel K, Fodor S. Pulmonary embolism and symptomatic psychosis.. Germ Med Mnth 1969; 14: 184-7.
• 29 Geerts WH, Code KI, Jay RM, Chen E, Szalai JP. A prospective study of venous thrombosis after major trauma.. New Engl J Med 1994; 331: 1601-6.
• 30 Meer van der FJM, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors.. Arch Intern Med 1993; 153: 1557-62.
• 31 Fihn SD. Aiming for safe anticoagulation.. New Engl J Med 1995; 333: 54-5.
• 32 Hille ETM, Westendorp RGJ, Vandenbroucke JP, Rosendaal FR. Mortality and causes of death in families with the factor V Leiden mutation (Resistance to activated protein C).. Blood 1997; 89: 1963-7.
• 33 Vandenbroucke JP, van der Meer FJM, Helmerhorst FM, Rosendaal FR. Factor V Leiden: should we screen oral contraceptive users and pregnant women?. Brit Med J 1996; 313: 1127-30.