APC Resistance in Childhood Thromboembolism: Diagnosis and Clinical Aspects

Nowak‐Göttl, Ulrike; Schneppenheim, Reinhard; Vielhaber, H.

doi:10.1055/s-2007-996098

Cited by 18 publications

(8 citation statements)

References 31 publications

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“…Even so, the FV : Q506 allele is still a risk factor for thrombosis in children and even neonates. [144][145][146][147] Several studies have demonstrated the presence of the FV : Q506 allele in around 50% of children with venous thromboembolism. 147,148…”

Section: Epidemiology and Clinical Manifestations Of Apc Resistancementioning

confidence: 99%

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Dahlbäck¹

1999

Semin Thromb Hemost

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Inherited resistance to activated protein C (APC) is the most common genetic risk factor of venous thrombosis. It is caused by a single point mutation in the factor (F)V gene which predicts replacement of Arg506 with a Gln (FVR506Q, FV: Q506 or FV Leiden). This mutation affects the function of the protein C system, a physiologically important natural anticoagulant pathway. APC inhibits coagulation by cleaving a limited number of peptide bonds in both intact and activated forms of factor V (FV/FVa) and factor VIII (FVIII/FVIIIa). Degradation of FVa by APC is stimulated by protein S, whereas inactivation of FVIIIa requires the synergistic cofactor function of protein S and FV proteolytically modified by APC. Thus, FV has the potential to express opposing functions, as a procoagulant after cleavage by thrombin or FXa and as an anticoagulant after cleavage by APC. The FVR506Q mutation not only confers partial resistance of FVa to APC but also impairs the degradation of FVIIIa because APC-mediated cleavage of FV at Arg506 is required for expression of the anticoagulant activity of FV. The impaired degradation of both FVIIIa and FVa yield a hypercoagulable state conferring a lifelong increased risk of thrombosis. The FV mutation is common in Caucasians, whereas it is rarely found among other groups worldwide. In patients with severe thrombophilia having other inherited defects such as deficiencies of protein S, protein C, or antithrombin, APC resistance is often found as a contributing genetic risk factor. Individuals with combined genetic defects have a high risk of thrombosis, and it is now generally accepted that thrombophilia is a multigenetic disease.

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Section: Epidemiology and Clinical Manifestations Of Apc Resistancementioning

confidence: 99%

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Dahlbäck¹

1999

Semin Thromb Hemost

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“…There are several congenital defects of the coagulation system that in conjunction with other risk factors may predispose children to an increased rate of VTE. 2,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] The well-recognized defects include deficiencies of PC, PS, AT, plasminogen, and the presence of activated protein C resistance (APCR), which is primarily due to FV Leiden, and the prothrombin gene variant 20210 Gln→Arg. 35 FV Leiden causing APCR is the most prevalent congenital prothrombotic defect in adults with VTE and represents a single-point mutation in the FV gene that significantly slows the inactivation of FVa.…”

Section: Congenital Disordersmentioning

confidence: 99%

Venous Thromboembolism in Pediatrics

Anton

Massicotte²

2001

Seminars in Vascular Medicine

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Venous thromboembolism (VTE) in pediatrics is quickly becoming a well-recognized cause of significant morbidity and mortality in children. Most children diagnosed with VTE have a serious underlying primary illness such as cancer, chronic total parenteral nutrition (TPN) dependency, or congenital heart disease. Infants and adolescents are most at risk of developing VTE, and the most significant risk factor is the presence of a central venous line (CVL). The incidence of VTE varies widely with study design and the diagnostic test used to detect thrombosis. Venography remains the gold standard diagnostic test, although ultrasound is increasingly used due to its noninvasive nature, despite concern regarding the sensitivity in upper system VTE. The treatment of uncomplicated VTE in children consists primarily of unfractionated heparin (UFH) initially, followed by oral anticoagulation or low molecular weight heparin (LMWH) for 3 months. LMWH offers many advantages over UFH due to the longer half-life, increased bioavailability, and ease of administration and monitoring in children. Acute complications of VTE in children are numerous and include pulmonary embolism (PE), chylothorax, and superior vena cava syndrome. Long-term morbidity includes recurrent VTE, postthrombotic syndrome, repeat general anesthetics for CVL placement, and eventual destruction of the upper venous system in children with repeat CVL-related VTE. Death from VTE is rare and is primarily due to PE.

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“…The increase in TAFI would imply that there may be some resistance to fibrinolysis. Nowak-Gottl et al (14) reported increased levels of DD in heterozygous FVL children and the au-thors, in unpublished data, found that heterozygous adults with history of ~ITE I~~d higher DD than patients without FVL. Pregnant women with FVL have higher incidence and risk of VTE than those without the mutation (15).…”

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confidence: 91%

State-of-the-Art Review: Thrombophilia and Pregnancy: Review of the Literature and Some Original Data

Arkel

2001

Clin Appl Thromb Hemost

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The association of thrombophilia with pregnancy complications has received increasing attention. It is now apparent that thrombophilia is responsible for a large number of the serious complications of pregnancy such as venous thrombosis, pulmonary embolism, fetal loss, pregnancy loss, intrauterine fetal demise, and preeclampsia. The inherited thrombophilia abnormalities, factor V Leiden mutation, prothrombin gene mutation 20210A, and antithrombin III, protein C, and protein S deficiency, and the acquired disorders, the anticardiolipin syndrome and lupus inhibitor, are responsible for a large share of the incidences of premature termination of pregnancy and many of the above complications. The normal physiology of pregnancy may be prothrombotic, with evidence for increased markers of activated coagulation and coagulation factors. There is a decrease in protein S and resistance to activated protein C occurs in a significant number of pregnancies in the absence of the factor V Leiden mutation. In the following article, we review some of the major studies that have correlated the thrombophilia and other acquired disorders that adversely impact pregnancies.

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APC Resistance in Childhood Thromboembolism: Diagnosis and Clinical Aspects

Cited by 18 publications

References 31 publications

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Venous Thromboembolism in Pediatrics

State-of-the-Art Review: Thrombophilia and Pregnancy: Review of the Literature and Some Original Data

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