Copyright 1997 by the American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use. American Medical Association, 515 N. State St, Chicago, IL 60610.
Volume 133(8)             August 1997             pp 1051-1052
Thrombotic Klinefelter Syndrome Associated With Factor V Leiden Mutation
[Correspondence: Vignettes]

Depaire-Duclos, Florence MD; Gris, Jean Charles MD, PhD; Dandurand, Michel MD; Guillot, Bernard MD

Hopital Nimes, F 30029 Cedex, Nimes, France (Depaire-Duclos, Gris, Dandurand, Guillot).

Outline

Five major inherited disorders are considered risk factors for recurrent venous thrombosis: protein C, protein S, or antithrombin III deficiency, hyperhomocystinemia, and activated protein C (APC) resistance. In 1993, Dahlback [1] noted that the addition of APC to plasma obtained from a patient with recurrent thrombosis, without any previously recognized thrombotic disorder, did not prolong the activated partial thromboplastin time as occurred when APC was added to plasma from healthy individuals. The term APC resistance was used to describe this patient. Most patients with APC resistance have a mutant factor V molecule (Leiden mutation) that resists proteolysis by APC when activated to factor Va. This resistance is the result of a specific point mutation (replacement of arginine 506 by glutamine) in the gene coding for coagulation factor V. Not all patients with APC resistance will experience thrombosis. Additional genetic defects or exogenous factors may be necessary to induce thrombosis in patients with APC resistance. Patients homozygous for the factor V Leiden mutation have a diminished response to APC compared with heterozygous and normal patients. Activated protein C resistance should be determined by the APC ratio (calculated by dividing the activated partial thromboplastin time, measured after the addition of APC, by the time recorded without APC). This procedure should be performed without anticoagulant therapy, and false-positive results may be obtained (due to factor deficiencies or lupus anticoagulants). [1,2]

Klinefelter syndrome (KS) is caused by the presence of at least one extra X chromosome and it affects approximately 1 in 500 males. Leg ulcers, with or without signs of venous insufficiency or obesity, and a high prevalence of venous thromboembolic disease have been reported in patients with KS. Different hemostatic disorders (platelet hyperaggregability and abnormal fibrinolysis) have been reported as possible factors in the pathogenesis of leg ulceration in patients with KS. [3-5]

Report of a Case. A 62-year-old patient was admitted to the hospital because of recurrent venous thrombosis, pulmonary embolism, and bilateral leg ulcers for 10 years. He did not have varicose veins but bilateral postthrombotic syndrome was found with a duplex ultrasonographic investigation (persistent obstruction in the sural and popliteal veins without valvate incompetency). A chromosome analysis revealed a 47, XXY karyotype, confirming the clinical diagnosis of KS. The patient's testosterone level was low and diet-controlled hyperglycemia was noted. Before androgen replacement therapy and anticoagulation treatment were initiated, an insufficient fibrinolytic response to a 10-minute venous occlusion test was noted (euglobulin clot lysis time before venous occlusion, 180 minutes; after venous occlusion, 135 minutes; tissue-type plasminogen activator-related antigen level before stasis, 12.9 micrograms/mL; after stasis, 47.9 micrograms/mL). We did not note any beneficial role of androgen replacement therapy in the healing of his leg ulcers. Recently, the patient was found to be heterozygous for the factor V DNA mutation R 506 Q (Leiden mutation), despite a normal response to APC as assessed by the APC ratio (3.2; normal range, 2.4-3.5).

Comment. Venous thromboembolism is obviously a multifactorial process and additional factors are necessary to induce symptomatic events in patients with inheritable thrombophilia, eg, APC resistance. The factor V Leiden mutation is frequently detected in patients older than 60 years with a first episode of thrombosis. To our knowledge, we report for the first time the association of the mutation with KS. The association of KS and APC resistance should be fortuitous but could be considered an additional risk factor for the development of recurrent thrombosis. We suggest that patients with KS and thrombosis, a clinical risk factor for deep vein thrombosis, should be investigated for APC resistance and the factor V Leiden mutation.

Florence Depaire-Duclos, MD

Jean Charles Gris, MD, PhD

Michel Dandurand, MD

Bernard Guillot, MD

Hopital Nimes, F 30029 Cedex, Nimes, France

REFERENCES^
1. Dahlback B. Molecular genetics of thrombophilia: factor V gene mutation causing resistance to activated protein C as a basis of the hypercoagulable state.J Lab Clin Med. 1995;125:566-571. [Medline Link] [BIOSIS Previews Link] [Context Link]

2. Rodgers GM. Activated protein C resistance and inherited thrombosis. Am J Clin Pathol. 1995;103:261-262. [Medline Link] [Context Link]

3. Hesse S, Berbis S, Juhan-Vague I, et al. Syndrome de Klinefelter et ulceres de jambe: place des troubles de l'hemostase. Ann Dermatol Venereol. 1992;119:951-957. [Medline Link] [Context Link]

4. Veraart JC, Hamulyak K, Neumann HA. Leg ulcers and Klinefelter's syndrome. Arch Dermatol. 1995;131:958-959. [Fulltext Link] [Medline Link] [Context Link]

5. Higgins EJ, Tidman MJ, Savidge GF, et al. Platelet hyperaggregability in two patients with Klinefelter's syndrome complicated by leg ulcers. Br J Dermatol. 1989;120:322. [Medline Link] [Context Link]

Factor V Leiden; Klinefelter Syndrome; Mutation; Pulmonary Embolism; Thrombophlebitis; Venous Thrombosis