Combined heterozygote factor V Leiden mutation and anticardiolipin antibody positivity in a young patient with spontaneous deep vein thrombosis/Kombine heterozigot faktor V Leiden mutasyonu ve antikardiyolipin antikor pozitifligi olan genc bir hastada derin ven trombozu.

Introduction

In this report, we present an interesting case of a combined heterozygote factor V Leiden mutation and anticardiolipin antibody positivity in a young patient with spontaneous deep vein thrombosis, which emphasizes importance of thrombophilia.

Case Report

A 21-year-old male was referred to our hospital because of an acute onset pain on his lower extremities. He had no previous medical history and no precipitating condition such as trauma, surgical procedure or immobility. Also he had no history of alcohol or cigarette consumption. His father had a coronary artery disease and his mother had a history of two spontaneous abortions.

On physical examination, he had painful thighs and positive Homan's signs on both lower extremities. There was no other abnormal sign. On venous Doppler ultrasound, deep venous thromboses were established, extending from the calf veins through the popliteal, superficial, and common femoral veins and into external iliac veins (Fig. 1, 2). After taking venous blood samples, low molecular weight heparin was implemented to the patient.

Abnormal laboratory tests were as follows: a polymerase chain reaction revealed heterozygosity for factor V Leiden. Among other tests, lupus anticoagulant test was negative. The patient had normal antithrombin III, protein S and C levels as well. Anticardiolipin antibody (aCL) immunoglobulin M (IgM): 46.3 MPL units (normal <9 MPL units) and aCL immunoglobulin G (IgG) 23 MPL units (normal <9 MPL units).

His symptoms subsided in few days after the anticoagulant treatment. He was then switched to warfarin treatment and discharged on warfarin to be taken indefinitely. In the follow up period his symptoms completely resolved and he had not any further thromboembolic event during one year of follow-up.

Discussion

Thrombophilia is an either inherited or acquired tendency for venous thromboembolism. An early age (<45 years) thrombosis without any precipitating condition, especially at unusual sites are the clinical features suggesting thrombophilia.

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Factor V Leiden mutation is present in the 4-6% of the general population and is the most common inherited cause of the syndrome accounting for the 40-50% of cases (1). The heterozygosity of factor V Leiden is associated with three to seven fold increased risk of venous thromboembolism (2). Other less common causes of inherited thrombophilia are the antithrombin III, protein C and S deficiencies, and rare conditions such as plasminogen and heparin cofactor-II deficiencies and dysfibrinogenemia. However, the lifetime probability of developing thrombosis and the severity of the thromboses seem to be considerably less in heterozygotes with the factor V Leiden mutation than in patients with the less common inherited thrombophilias (3). Moreover, there is an increased incidence of factor V Leiden among thrombotic patients with other thrombophilic defects, as compared to the general population. The presence of additional inherited defects increases the thrombotic risk comparing to single factor V Leiden mutation (4, 5). The acquired risk factors such as oral contraceptives, hormone replacement therapy and pregnancy also increase the risk of thrombosis when they are together with factor V Leiden mutation (6).

Although there are numerous reports regarding both inherited and acquired thrombotic risk factors combined with Factor V Leiden mutation, we have not noticed any data about the association of ACA and Factor V Leiden mutation. Our search for the Medline revealed a case report about an association of Factor V Leiden mutation and lupus anticoagulant in a young man who developed lower extremity deep vein thrombosis (7). The present report about the association of high ACA and Factor V Leiden mutation is therefore puts forward an uncommon association in the risk of thrombophilia. Yet, there is some conflicting data about the role of ACA or lupus anticoagulants on the risk of thrombophilia. Antiphospholipid antibodies can be detected in approximately 5 to 21 percent of all patients with venous thrombosis, although this does not necessarily point out a casual relationship. There are however, reports regarding the increased risk of deep venous thrombosis due to the presence of lupus anticoagulant or ACA, and a recent meta-analysis showed that the risk for anti phospholipid associated thrombosis demonstrated a higher risk in patients with the lupus anticoagulant and aCL than in other patients (8).

Because of the above data, we considered that the cause of the massive deep vein thrombosis of our case was the combination of Factor V Leiden mutation and high aCL IgG and IgM levels. As the patient had two permanent risk factors of venous thrombosis we decided to continue the anticoagulation indefinitely.

Bili et al. coworkers (9) represented the largest study to date evaluating the association between aCL and a[beta]2GPI antibodies and recurrent cardiac events in patients after myocardial infarction . Factor V Leiden is a risk factor for MI in young people, because of its high prevalence compared with other genetic mutations relevant to thrombosis, the effect of factor V Leiden in populations of other age and sex, in association with other risk factors (10). These data also revealed an inverse association of IgM aCL antibody levels with recurrent cardiac events (9). Thus, patients with elevated IgG aCL and low IgM aCL antibodies had the highest risk compared with all other aCL antibody groups.

Conclusion

We conclude that young patients with spontaneous venous thrombosis should be meticulously investigated for the presence of both hereditary and acquired thrombotic risk factors. This situation suggested these patients should be evaluated by physicians for cardiovascular events.

References

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(3.) Lensen RP, Rosendaal FR, Koster T, Allaart CF, de Ronde H, Bertina RM. Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients. Blood 1996; 88: 4205-8.

(4.) Koeleman BPC, 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.

(5.) Koeleman BPC, van Rumpt D, Hamulyak K, Reitsma PH, Bertina RM. Factor V Leiden: an additional risk factor for thrombosis in protein S deficient families? Thromb Haemost 1995; 74: 580-3.

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(7.) Lopez FF, Sweeney JD, Blair AJ, Sikov WM. Spontaneous venous thrombosis in a young patient with combined factor V Leiden and lupus anticoagulant. Am J Hematol 1999; 62: 58-60.

(8.) Wahl DG, Guillemin F, de Maistre E, Perret-Guillaume C, Lecompte T, Thibaut G. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15-22.

(9.) Bili A, Moss AJ, Francis CW, Zareba W, Watelet LF, Sanz I. Anticardiolipin antibodies and recurrent coronary events: a prospective study of 1150 patients. Thrombogenic Factors, and Recurrent Coronary Events Investigators. Circulation 2000; 102: 1258-63.

(10.) Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-21.

Nuri Karadurmus, Cengiz Ozturk *, Alper Sonmez **, Teoman Dogru **, Satilmis Inal, Canturk Tasci, Ahmet Ozturk **, Selahattin Erikci **

From Departments of Internal Medicine and * Cardiology, Military Hospital, Eskisehir ** Department of Internal Medicine, Gulhane Military Academy, Ankara, Turkey

Address for Correspondence/Yazisma Adresi: Cengiz Ozturk, MD, Department of Cardiology, Military Hospital 26040, Eskisehir, Turkey Phone: [phone] Fax: [phone] E-mail: [e-mail]