Factor V Leiden and Thromboembolism
To the Editor:
In an excellent study, Ridker et al1 recently demonstrated that the risk of thrombosis is greatly increased when the factor V Leiden mutation and hyperhomocysteinemia, which alone are only moderate risk factors for thrombosis, occur together. As stated in the accompanying editorial by Phillips,2 a potential weakness of this study is that the activity of other anticoagulant and fibrinolytic proteins was not specifically reported. We present a case of a 33-year-old man with factor V Leiden, increased plasminogen activator inhibitor 1 (PAI-1) activity, and a history of multiple thromboembolic events.
At the age of 18 years, the patient had pulmonary embolism of unknown origin when he was hospitalized for urologic surgery. At the age of 24 years, he developed a deep venous thrombosis without evidence of trauma complicated also on this occasion by pulmonary embolism. Warfarin was administered for 6 months. However, detailed investigations of the hypercoagulable state were not performed. At the age of 29 years, the patient was admitted with chest pain and acute inferior myocardial infarction diagnosed by ECG. Despite thrombolysis, the patient developed a maximum creatinine kinase level of 515 U/L with an MB fraction of 15%. Coronary angiography was performed 3 weeks after the myocardial infarction and revealed normal coronary arteries (see Figure⇓ ), suggesting that the infarction had been caused by a thrombotic occlusion and not by rupture or dissection of an atheromatous plaque. Six months after the infarction, the patient was referred to our institution for assessment of potential risk factors. He was a nonsmoker, had normal blood pressure, and was overweight (body mass index, 31.3 kg/m3). Lipid levels were normal (total cholesterol, 114 mg/dL; triglycerides, 80 mg/dL; LDL cholesterol, 51 mg/dL; HDL cholesterol, 47 mg/dL; lipoprotein(a), 11 mg/dL). Investigation for a hypercoagulable state showed normal values of fibrinogen (260 mg/dL), antithrombin III activity (84%), plasminogen (101%), protein C activity (91%), and protein S activity (96%). The activity of PAI-1 was increased (5.1 U/mL; reference range: 0.3 to 3.5 U/mL). In addition, the patient showed activated protein C (APC) resistance (APC ratio, 1.8; reference limit >2.0) associated with heterozygosity for factor V Leiden. A family history revealed that the sister of the patient had died at the age of 36 years from sudden cardiac death. The patient’s mother had a history of six venous thromboses, four of which occurred during pregnancy and the remaining two of which occurred without obvious precipitating factors. She was identified as a carrier of factor V Leiden and had an increased fibrinogen of 475 mg/dL. PAI-1 and all other laboratory parameters were normal. The following relatives who had only one risk factor interfering with the coagulation system had no history of thromboembolism: The patient’s father had an increased fibrinogen (476 mg/dL) and no other risk factors. The patient’s sister and brother both showed an increased fibrinogen of 394 and 402 mg/dL, respectively, but no other risk factors. The risk profile of the patient’s 5- and 9-year-old daughters was normal except for heterozygosity for the factor V mutation in the 5-year-old daughter.
These data support the concept that increased thrombotic risk arises from the synergistic interaction of a number of risk factors. The occurrence of a myocardial infarction in our index patient was unexpected because epidemiologic studies did not show a higher prevalence of factor V Leiden in patients after myocardial infarction.3 4 However, it cannot be excluded entirely that factor V Leiden, in rare instances, causes not only venous but also arterial thrombosis. It is possible that such patients suffer from myocardial infarction at a very young age and have therefore been missed in the cohort studies performed up to now.
- Copyright © 1998 by American Heart Association
Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocystinemia, factor V Leiden, and risk of future venous thromboembolism. Circulation. 1997;95:1777–1782.
Phillips MD. Interrelated risk factors for venous thromboembolism. Circulation. 1997;95:1749–1751. Editorial.
My colleagues and I appreciate the kind words of Drs Walter, Reinecke, Heinrich, Breithardt, and Assmann concerning our description of markedly increased risks of venous thromboembolism among individuals with both factor V Lieden and hyperhomocystinemia.R1 Indeed, as discussed elsewhere, the evolving epidemiology of hemostasis and thrombosis clearly indicates that thromboembolism is more likely to occur among those with multiple defects of the anticoagulation and fibrinolytic systems.R2 Such defects can be permanent (genetic), acquired (antibody related), or transient (pregnancy).
With specific regard to PAI-1 antigen and tissue plasminogen activator antigen, we note that prior work from our group found no evidence of association between these parameters and risks of venous thrombosis.R3 On the other hand, we and others have found PAI-1 antigen and/or tissue plasminogen activator antigen to be strong markers of risk for arterial thrombosis.R4 R5 R6 R7 Thus the observation of acute myocardial infarction in the patient described with both factor V Leiden and evidence of hypofibrinolysis is intriguing. From a clinical perspective, evaluations for such hypercoagulable interactions should generally be performed with the patient discontinued from warfarin therapy.
It is of importance that a careful distinction be made between venous and arterial thrombosis. Specific defects of hemostasis tend to be risk factors only for venous thrombosis or only for arterial thrombosis, but not both. Hyperhomocystinemia appears to be one of the few factors with substantial effects on clinical events in both the arterial and venous systems.
Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risks of future venous thromboembolism. Circulation. 1997;95:1777–1782.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Shen C, Newcomer LM, Goldhaber SZ, Hennekens CH. Baseline fibrinolytic state and the risk of future venous thrombosis: a prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor. Circulation. 1992;85:1822–1827.
Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW, for the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635–641.
Juhan-Vague I, Pyke SDM, Alessis MC, Jespersen J, Haverkate F, Thompson SG, on behalf of the ECAT Study Group. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation. 1996;94:2057–2063.