84 Case report
Heerlen polymorphism associated with type III protein S deficiency and factor V Leiden mutation in a Polish patient with deep vein thrombosis Ewa Wypaseka,b, Daniel P. Potaczeka, Martine Alhenc-Gelasc and Anetta Undasa,b Protein S is one of the major natural anticoagulants. A missense serine 501 to proline (S501P) Heerlen polymorphism is associated with reduced levels of free protein S. Heerlen polymorphism, especially when combined with other thrombophilia risk factors, can lead to thromboembolic complications. To our knowledge, we report here the first Polish case associated with heterozygous Heerlen polymorphism resulting in type III protein S deficiency, detected in a 50-year-old man with several thrombotic episodes of deep and superficial veins and a highly positive thrombotic family history. The patient also had factor V Leiden mutation and persistently elevated anticardiolipin antibodies. It seems that increased risk of thrombotic complications could be explained in the patient by a synergy between the effects of Heerlen polymorphism, factor V Leiden heterozygous status and antiphospholipid
Introduction Protein S is a vitamin K-dependent plasma natural anticoagulant. Approximately 60% of the total protein S is inactive by forming a noncovalent complex with the C4bbinding protein. The remaining 40% of free protein S acts as a cofactor for activated protein C (APC) in the proteolytic degradation of activated factor (F)V and FVIII [1]. In addition, protein S stimulates tissue factor pathway inhibitor (TFPI) in the inactivation of FXa [2]. Protein S deficiency is an autosomal dominant disorder with a prevalence of less than 0.5% in the general European population and 2–12% in patients with deep-vein thrombosis (DVT) or pulmonary embolism [3]. Protein S deficiency is classified as type I (low total and free antigen, reduced activity), type II (normal total and free antigen, reduced activity) and type III (normal total antigen, reduced free antigen and activity) [1]. Many types of gene defects including point mutations and small insertions/ deletions have been identified in the protein S gene (PROS1; chromosome 3q11.2, NCBI Gene, http://www. ncbi.nlm.nih.gov/gene), which are considered causative of a protein S-deficient phenotype (HGMD database, http:// www.hgmd.org). Acquired protein S deficiency can develop with vitamin K deficiency, liver disease, treatment with vitamin K antagonists, severe and chronic inflammation or autoimmune syndromes [4]. Here, we report a case of protein S deficiency resulting from S501P (HGVS numbering system) mutation 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
syndrome. Blood Coagul Fibrinolysis 25:84–85 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:84–85 Keywords: deep vein thrombosis, factor V Leiden, Heerlen polymorphism, protein S deficiency a
The John Paul II Hospital, bInstitute of Cardiology, Jagiellonian University Medical College, Krako´w, Poland and cHe´matologie biologique, AP-HP Hoˆpital Europe´en G. Pompidou, Paris, France Correspondence to Anetta Undas, Institute of Cardiology, Jagiellonian University Medical College, 80 Pra˛dnicka St., 31-202 Krako´w, Poland Tel: +48 12 6143004; fax: +48 12 4233900; e-mail: [email protected] Received 4 June 2013 Revised 10 July 2013 Accepted 11 July 2013
(Heerlen polymorphism) in the PROS1 gene diagnosed in a Polish patient.
Case report A 50-year-old overweight man with recurrent DVT was referred to our Center for Coagulation Disorders. He experienced the first unprovoked thrombosis in the calf veins of the right leg at the age of 38. Another thrombotic episode in the same location occurred at the age of 49 and was successfully treated with enoxaparin for 3 months. Then, the patient had two episodes of superficial thrombosis of varicose veins on the right leg, which were also treated with a short-term administration of enoxaparin. The patient refused anticoagulation with vitamin K antagonists and was taking low-dose aspirin. During the last year, no thrombotic episode was observed. He had no comorbidities. Routine laboratory tests were normal. Family history for thrombosis was positive. The proband’s grandmother and her father died of pulmonary embolism at the age of about 45. His mother and daughter also experienced unprovoked DVT. Thrombophilia screening was performed. Factor V Leiden (FVL) mutation was present at the heterozygous state and F2 gene G20210A mutation was absent. Deficiencies in protein C and antithrombin were excluded. Factor VIII activity and total homocysteine were within normal limits. Lupus anticoagulant, DOI:10.1097/MBC.0b013e328365032c
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Heerlen polymorphism in a Polish patient Wypasek et al. 85
antib2-glycoprotein I antibodies, both in IgG and IgM classes, and anticardiolipin IgG antibodies were negative. The IgM anticardiolipin antibody levels were raised and sustained [49.3 and 54.3 MPL, normal (N)
Heerlen polymorphism associated with type III protein S deficiency and factor V Leiden mutation in a Polish patient with deep vein thrombosis Ewa Wypaseka,b, Daniel P. Potaczeka, Martine Alhenc-Gelasc and Anetta Undasa,b Protein S is one of the major natural anticoagulants. A missense serine 501 to proline (S501P) Heerlen polymorphism is associated with reduced levels of free protein S. Heerlen polymorphism, especially when combined with other thrombophilia risk factors, can lead to thromboembolic complications. To our knowledge, we report here the first Polish case associated with heterozygous Heerlen polymorphism resulting in type III protein S deficiency, detected in a 50-year-old man with several thrombotic episodes of deep and superficial veins and a highly positive thrombotic family history. The patient also had factor V Leiden mutation and persistently elevated anticardiolipin antibodies. It seems that increased risk of thrombotic complications could be explained in the patient by a synergy between the effects of Heerlen polymorphism, factor V Leiden heterozygous status and antiphospholipid
Introduction Protein S is a vitamin K-dependent plasma natural anticoagulant. Approximately 60% of the total protein S is inactive by forming a noncovalent complex with the C4bbinding protein. The remaining 40% of free protein S acts as a cofactor for activated protein C (APC) in the proteolytic degradation of activated factor (F)V and FVIII [1]. In addition, protein S stimulates tissue factor pathway inhibitor (TFPI) in the inactivation of FXa [2]. Protein S deficiency is an autosomal dominant disorder with a prevalence of less than 0.5% in the general European population and 2–12% in patients with deep-vein thrombosis (DVT) or pulmonary embolism [3]. Protein S deficiency is classified as type I (low total and free antigen, reduced activity), type II (normal total and free antigen, reduced activity) and type III (normal total antigen, reduced free antigen and activity) [1]. Many types of gene defects including point mutations and small insertions/ deletions have been identified in the protein S gene (PROS1; chromosome 3q11.2, NCBI Gene, http://www. ncbi.nlm.nih.gov/gene), which are considered causative of a protein S-deficient phenotype (HGMD database, http:// www.hgmd.org). Acquired protein S deficiency can develop with vitamin K deficiency, liver disease, treatment with vitamin K antagonists, severe and chronic inflammation or autoimmune syndromes [4]. Here, we report a case of protein S deficiency resulting from S501P (HGVS numbering system) mutation 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
syndrome. Blood Coagul Fibrinolysis 25:84–85 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:84–85 Keywords: deep vein thrombosis, factor V Leiden, Heerlen polymorphism, protein S deficiency a
The John Paul II Hospital, bInstitute of Cardiology, Jagiellonian University Medical College, Krako´w, Poland and cHe´matologie biologique, AP-HP Hoˆpital Europe´en G. Pompidou, Paris, France Correspondence to Anetta Undas, Institute of Cardiology, Jagiellonian University Medical College, 80 Pra˛dnicka St., 31-202 Krako´w, Poland Tel: +48 12 6143004; fax: +48 12 4233900; e-mail: [email protected] Received 4 June 2013 Revised 10 July 2013 Accepted 11 July 2013
(Heerlen polymorphism) in the PROS1 gene diagnosed in a Polish patient.
Case report A 50-year-old overweight man with recurrent DVT was referred to our Center for Coagulation Disorders. He experienced the first unprovoked thrombosis in the calf veins of the right leg at the age of 38. Another thrombotic episode in the same location occurred at the age of 49 and was successfully treated with enoxaparin for 3 months. Then, the patient had two episodes of superficial thrombosis of varicose veins on the right leg, which were also treated with a short-term administration of enoxaparin. The patient refused anticoagulation with vitamin K antagonists and was taking low-dose aspirin. During the last year, no thrombotic episode was observed. He had no comorbidities. Routine laboratory tests were normal. Family history for thrombosis was positive. The proband’s grandmother and her father died of pulmonary embolism at the age of about 45. His mother and daughter also experienced unprovoked DVT. Thrombophilia screening was performed. Factor V Leiden (FVL) mutation was present at the heterozygous state and F2 gene G20210A mutation was absent. Deficiencies in protein C and antithrombin were excluded. Factor VIII activity and total homocysteine were within normal limits. Lupus anticoagulant, DOI:10.1097/MBC.0b013e328365032c
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Heerlen polymorphism in a Polish patient Wypasek et al. 85
antib2-glycoprotein I antibodies, both in IgG and IgM classes, and anticardiolipin IgG antibodies were negative. The IgM anticardiolipin antibody levels were raised and sustained [49.3 and 54.3 MPL, normal (N)
