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Factor V Leiden Thrombophilia Jody Lynn Kujovich, MD

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Factor V Leiden Thrombophilia Jody Lynn Kujovich, MD GENETEST REVIEW Genetics in Medicine Factor V Leiden thrombophilia Jody Lynn Kujovich, MD TABLE OF CONTENTS Pathogenic mechanisms and molecular basis.................................................2 Obesity ...........................................................................................................8 Prevalence..............................................................................................................2 Surgery...........................................................................................................8 Diagnosis................................................................................................................2 Thrombosis not convincingly associated with Factor V Leiden....................8 Clinical diagnosis..............................................................................................2 Arterial thrombosis...........................................................................................8 Testing................................................................................................................2 Myocardial infarction.......................................................................................8 Indications for testing......................................................................................3 Stroke .................................................................................................................8 Natural history and clinical manifestations......................................................3 Genotype-phenotype correlations.....................................................................8 Venous thromboembolism .............................................................................3 Factor V Leiden and Factor V deficiency......................................................8 Risk for a first VTE.............................................................................................4 HR2 haplotype ..................................................................................................9 Recurrent VTE....................................................................................................4 Genetically related (allelic) disorders ................................................................9 Pregnancy complications ................................................................................4 Penetrance.............................................................................................................9 Pregnancy loss ..............................................................................................5 Differential diagnosis ...........................................................................................9 Other obstetric complications....................................................................5 Inherited disorders ...........................................................................................9 Clinical expression of Factor V Leiden ..............................................................5 Acquired disorders .........................................................................................10 Coexisting thrombophilic disorders ..............................................................5 Management ......................................................................................................10 Circumstantial risk factors...............................................................................6 Evaluation after initial diagnosis ..................................................................10 Central venous catheters.............................................................................6 Treatment of manifestations ........................................................................10 Pregnancy......................................................................................................6 Prevention of primary manifestations.........................................................11 Oral contraceptives ......................................................................................6 Pregnancy........................................................................................................11 Hormone replacement therapy..................................................................7 Prevention of pregnancy complications.....................................................11 Selective estrogen receptor modulators...................................................7 Genetic counseling ............................................................................................11 Travel..............................................................................................................7 Proband heterozygous for Factor V Leiden ...............................................11 Age..................................................................................................................7 Proband homozygous for Factor V Leiden ................................................11 Minor injury...................................................................................................7 Testing at-risk family members....................................................................11 Abstract: Factor V Leiden is a genetic disorder characterized by a poor tion may be considered in high-risk clinical settings. In the absence of anticoagulant response to activated Protein C and an increased risk for evidence that early diagnosis reduces morbidity or mortality, decisions venous thromboembolism. Deep venous thrombosis and pulmonary regarding testing at-risk family members should be made on an indi- embolism are the most common manifestations, but thrombosis in vidual basis. Genet Med 2011:13(1):1–16. unusual locations also occurs. The current evidence suggests that the Key Words: Factor V Leiden, thrombophilia, APC resistance, venous mutation has at most a modest effect on recurrence risk after initial thrombosis, anticoagulation treatment of a first venous thromboembolism. Factor V Leiden is also associated with a 2- to 3-fold increased relative risk for pregnancy loss and possibly other obstetric complications, although the probability of a enous thromboembolism (VTE; deep venous thrombosis successful pregnancy outcome is high. The clinical expression of Factor V[DVT] and/or pulmonary embolism) is a major medical V Leiden is influenced by the number of Factor V Leiden alleles, problem, which affects approximately 1 in 1000 persons per coexisting genetic and acquired thrombophilic disorders, and circum- year. VTE is a multicausal disease that results from multiple stantial risk factors. Diagnosis requires the activated Protein C resis- interactions between genetic, acquired, and circumstantial risk fac- tance assay (a coagulation screening test) or DNA analysis of the F5 tors. Thrombophilic disorders can be identified in half of patients gene, which encodes the Factor V protein. The first acute thrombosis is presenting with venous thrombosis. Inherited thrombophilia is a treated according to standard guidelines. Decisions regarding the opti- genetically determined tendency to develop VTE, which is often mal duration of anticoagulation are based on an individualized assess- recurrent. Inherited deficiencies of antithrombin, Protein C, and ment of the risks for venous thromboembolism recurrence and antico- Protein S are relatively rare and together account for Ͻ10% of agulant-related bleeding. In the absence of a history of thrombosis, patients with venous thrombosis. In 1993, Dahlba¨cketal.1 reported long-term anticoagulation is not routinely recommended for asymptom- an inherited poor response to the anticoagulant effect of activated atic Factor V Leiden heterozygotes, although prophylactic anticoagula- Protein C (APC) in several thrombosis prone families. The APC- resistant phenotype was prevalent among patients with venous From the Northwest Cancer Specialists, Portland, Oregon. thrombosis and subsequently shown to result from a single-point Jody Lynn Kujovich, MD, 265 N. Broadway, Portland, OR 97227. E-mail: mutation in the Factor V gene.2 [email protected]. Factor V Leiden is the most common genetic risk factor for Disclosure: The author declares no conflict of interest. VTE, found in 20–25% of patients with VTE and 50% of 3,4 Submitted for publication August 12, 2010. patients with familial thrombophilia. Testing for Factor V Leiden is now one of the most frequently ordered molecular Accepted for publication September 1, 2010. genetic tests. This review focuses on current data defining the Published online ahead of print November 24, 2010. thrombotic risks and complications associated with Factor V DOI: 10.1097/GIM.0b013e3181faa0f2 Leiden and its interaction with other genetic and acquired risk Genetics IN Medicine • Volume 13, Number 1, January 2011 1 Kujovich Genetics IN Medicine • Volume 13, Number 1, January 2011 factors. It also summarizes indications for testing and guidelines a,b for management and genetic counseling. Table 1 Worldwide prevalence of Factor V Leiden Population Prevalence (%)9–11,12–17 PATHOGENIC MECHANISMS AND MOLECULAR European whites 3–15 BASIS Spain 3.3 Factor V Leiden is a genetic disorder characterized by a poor France 3.8 anticoagulant response to APC. APC is a natural anticoagulant protein that cleaves and inactivates procoagulant Factors Va and Germany 4 VIIIa, thereby downregulating further thrombin generation.5,6 Iceland 5.2 APC inactivates Factor Va by cleavage at three different amino United Kingdom
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