(Circulation. 1998;97:1426-1427.)
© 1998 American Heart Association, Inc.
Factor V Leiden and Thromboembolism
Michael Walter, MD;
Holger Reinecke, MD;
Günter Breithardt, MD, FESC, FACC;
; Gerd Assmann, MD
Institute for Arteriosclerosis Research,
Institute of Clinical Chemistry and Laboratory Medicine,
Department of Cardiology and Angiology,
University Hospital of Münster, Germany
Jürgen Heinrich, PhD
Community Hospital Solingen, Germany
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.
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Figure 1. Coronary angiography was performed 3 weeks after
myocardial infarction. A, Left coronary artery; B, right
coronary artery.
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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.
References
1.
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.[Abstract/Free Full Text]
2.
Phillips MD. Interrelated risk factors for venous
thromboembolism. Circulation. 1997;95:1749–1751. Editorial.[Free Full Text]
3.
Ridker PM, Hennekens CH, Lindpainter 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;332:912–917.[Abstract/Free Full Text]
4.
Heinrich J, Budde T, Assmann G. Mutation in the factor V gene
and the risk of myocardial infarction. N Engl J
Med. 1995;333:880–881.[Free Full Text]
Response
Paul M. Ridker, MD
Division of Cardiovascular Diseases,
Brigham and Women's Hospital,
Boston, Mass
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.1 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.2 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.3 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.4 5 6 7 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.
References
1.
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.
2.
Ridker PM. Fibrinolytic and inflammatory markers for
arterial occlusion: the evolving
epidemiology of thrombosis and hemostasis.
Thromb Haemost. 1997;78:53–59.[Medline]
[Order article via Infotrieve]
3.
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.[Abstract/Free Full Text]
4.
Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH.
Endogenous tissue-type plasminogen
activator and risk of myocardial infarction.
Lancet. 1993;341:1165–1168.[Medline]
[Order article via Infotrieve]
5.
Hamsten A, Walldius G, Szamosi A, Blombäck M, de Faire U,
Dahlén G, Wiman B. Plasminogen activator
inhibitor in plasma: risk factor for recurrent myocardial
infarction. Lancet. 1987;2:3–9.[Medline]
[Order article via Infotrieve]
6.
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.[Abstract/Free Full Text]
7.
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.[Abstract/Free Full Text]
