Thrombophilia as a multigenic disease

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Thrombophilia as a multigenic disease. / Zöller, Bengt; Garcia de Frutos, Pablo; Hillarp, A; Dahlbäck, Björn.

I: Haematologica, Vol. 84, Nr. 1, 01.1999, s. 59-70.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Zöller, B, Garcia de Frutos, P, Hillarp, A & Dahlbäck, B 1999, 'Thrombophilia as a multigenic disease', Haematologica, vol. 84, nr. 1, s. 59-70.

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Zöller, Bengt ; Garcia de Frutos, Pablo ; Hillarp, A ; Dahlbäck, Björn. / Thrombophilia as a multigenic disease. I: Haematologica. 1999 ; Vol. 84, Nr. 1. s. 59-70.

RIS

TY - JOUR

T1 - Thrombophilia as a multigenic disease

AU - Zöller, Bengt

AU - Garcia de Frutos, Pablo

AU - Hillarp, A

AU - Dahlbäck, Björn

PY - 1999/1

Y1 - 1999/1

N2 - BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system.INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia.STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis.

AB - BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system.INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia.STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis.

KW - 3' Untranslated Regions

KW - Activated Protein C Resistance

KW - Adult

KW - Amino Acid Substitution

KW - Antithrombins

KW - Case Management

KW - Child

KW - Factor V

KW - Factor V Deficiency

KW - Female

KW - Gene Frequency

KW - Genetic Heterogeneity

KW - Genetic Predisposition to Disease

KW - Humans

KW - Infant, Newborn

KW - Male

KW - Mutation, Missense

KW - Phenotype

KW - Point Mutation

KW - Prevalence

KW - Protein C Deficiency

KW - Prothrombin

KW - Risk Factors

KW - Scandinavian and Nordic Countries

KW - Thrombophilia

KW - Thrombophlebitis

KW - Journal Article

KW - Review

M3 - Article

VL - 84

SP - 59

EP - 70

JO - Haematologica-The Hematology Journal

T2 - Haematologica-The Hematology Journal

JF - Haematologica-The Hematology Journal

SN - 1592-8721

IS - 1

ER -